Search

We previously identified three putative prophenoloxidase-activating proteinase (mdPAP1, mdPAP2, and mdPAP3) genes from housefly Musca domestica by transcriptomic analysis. In this study, mdPAP1 cDNA was cloned, and the function of its encoded protein was analyzed. The cDNA of mdPAP1 was 1358 bp, and it contained a single open reading frame of 1122 bp encoding a predicted MdPAP1 protein of 373 amino acids. The estimated molecular weight of MdPAP1 was 41267.08 Da with an isoelectric point of 6.25. The deduced amino acid sequence of MdPAP1 exhibited high similarity to known PAPs of insects. mdPAP1 was detected in larvae, pupae, and adult housefly, and the expression level of mdPAP1 was upregulated in bacterial challenged larvae. The recombinant protein of MdPAP1 expressed in Escherichia coli could cleave the prophenoloxidase into phenoloxidase in M. domestica hemolymph infected by bacteria and result in a significant increase of the total phenoloxidase activity. In addition, RNA interference-mediated gene silencing of mdPAP1 significantly increased the mortality of M. domestica larvae. Results indicated that mdPAP1 was involved in the activation of the prophenoloxidase against bacterial infection in M. domestica., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The objective of this study was to identify the main extended-spectrum beta-lactamase (ESBL)-producing bacteria and to detect the frequency of the major genes responsible to trigger this resistance in hospitalized animals. We collected 106 rectal swabs from cats ( n  = 25) and dogs ( n  = 81) to detect ESBL-producing isolates. ESBL-positive samples were submitted to the antimicrobial susceptibility test, and polymerase chain reaction was performed to detect TEM, SHV, and CTX-M genes from different groups. We observed that 44.34% of these samples (11 cats and 36 dogs) were positive for ESBL-producing bacteria. Thirteen animals (27.66%-seven cats and six dogs) were hospitalized for elective castration (healthy animals). Only a single animal was positive for ESBL-producing bacteria at hospital admission (the animal also showed an ESBL-positive isolate after leaving the hospital), whereas 11 were positive only at the hospital discharge. Of the 73 ESBL-producing isolates, 13 were isolated from cats (8 sick and 7 healthy) and 60 from dogs (53 sick and 7 healthy). Escherichia coli was the major ESBL-producing bacterium isolated (53.42%), followed by Pseudomonas aeruginosa (15.07%), Salmonella sp., and Proteus mirabilis (5.48% each one). Antimicrobial resistance profile of ESBL-producing isolates showed that 67 isolates (91.78%) were resistant to 3 or more antibiotic classes, while 13 of them (17.81%-2 healthy cats and 11 sick dogs) were resistant to all tested antimicrobial classes. The bla TEM gene exhibited the highest frequency in ESBL-producing isolates, followed by the bla CTX-M group 8/25, bla CTX-M group 1 and bla CTX-M group 9 genes. These results are useful to assess the predominance of ESBL-producing isolates recovered from dogs and in cats in Brazil. Consequently, we draw attention to these animals, as they can act as reservoirs for these microorganisms, which are the major pathogens of nosocomial infections worldwide.

The trehalose biosynthesis pathway has recently received attention for therapeutic intervention combating infectious diseases caused by bacteria, helminths or fungi. Trehalose-6-phosphate phosphatase (TPP) is a key enzyme of the most common trehalose biosynthesis pathway and a particularly attractive target owing to the toxicity of accumulated trehalose-6-phosphate in pathogens. Here, we characterised TPP-like proteins from bacterial pathogens implicated in nosocomial infections in terms of their steady-state kinetics as well as pH- and metal-dependency of their enzymatic activity. Analysis of the steady-state kinetics of recombinantly expressed enzymes from Acinetobacter baumannii, Corynebacterium diphtheriae and Pseudomonas stutzeri yielded similar kinetic parameters as those of other reported bacterial TPPs. In contrast to nematode TPPs, the divalent metal ion appears to be bound only weakly in the active site of bacterial TPPs, allowing the exchange of the resident magnesium ion with other metal ions. Enzymatic activity comparable to the wild-type enzyme was observed for the TPP from P. stutzeri with manganese, cobalt and nickel. Analysis of the enzymatic activity of S. maltophilia TPP active site mutants provides evidence for the involvement of four canonical aspartate residues as well as a strictly conserved histidine residue of TPP-like proteins from bacteria in the enzyme mechanism. That histidine residue is a member of an interconnected network of five conserved residues in the active site of bacterial TPPs which likely constitute one or more functional units, directly or indirectly cooperating to enhance different aspects of the catalytic activity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

β-Lactam antibiotics account for about 60% of all produced antibiotics. Due to a high activity and minimal side effects, they are the most commonly used class of antibacterial drugs for the treatment of various infectious diseases of humans and animals, including severe hospital infections. However, the emergence of bacteria resistant to β-lactams has led to the clinical inefficiency of these antibiotics, and as a result, their use in medicine has been limited. The search for new effective ways for overcoming the resistance to β-lactam antibiotics is an essential task. The major mechanism of bacterial resistance is the synthesis of β-lactamases (BLs) that break the antibiotic β-lactam ring. Here, we review specific inhibitors of serine β-lactamases and metallo-β-lactamases and discuss approaches for creating new inhibitors that would prolong the "life" of β-lactams.

The expression and localization of different isoforms of creatine kinase in Pelodiscus sinensis (PSCK) were studied to reveal the role of PSCK isozymes (PSCK-B, PSCK-M, PSCK-S) under bacterial infection-induced immunologic stress. The computational molecular dynamics simulations predicted that PSCK-S would mostly possess a kinase function in a structural aspect when compared to PSCK-B and PSCK-M. The assay of biochemical parameters such as total superoxide dismutase (T-SOD), lactate dehydrogenase (LDH), malondialdehyde (MDA), catalase (CAT), and the content of ATP were measured along with total PSCK activity in different tissue samples under bacterial infection. The expression detections of PSCK isozymes in vitro and in vivo were overall well-matched where PSCK isozymes were expressed differently in P. sinensis tissues. The results showed that PSCK-B mostly contributes to the spleen, followed by the liver and myocardium; PSCK-M mostly contributes to the liver, followed by the myocardium and skeletal muscle, while PSCK-S contributes to the spleen and is uniquely expressed in skeletal muscle. Our study suggests that the various alterations of PSCK isozymes in tissues of P. sinensis are prone to defense the bacterial infection and blocking energetic imbalance before severe pathogenesis turned on in P. sinensis., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Bacterial phosphothreonine lyases, or phospholyases, catalyze a unique post-translational modification that introduces dehydrobutyrine (Dhb) or dehydroalanine (Dha) in place of phosphothreonine or phosphoserine residues, respectively. We report the use of a phospha-Michael reaction to label proteins and peptides modified with Dha or Dhb. We demonstrate that a nucleophilic phosphine probe is able to modify Dhb-containing proteins and peptides that were recalcitrant to reaction with thiol or amine nucleophiles under mild aqueous conditions. Furthermore, we used this reaction to detect multiple Dhb-modified proteins in mammalian cell lysates, including histone H3, a previously unknown target of phospholyases. This method should prove useful for identifying new phospholyase targets, profiling the biomarkers of bacterial infection, and developing enzyme-mediated strategies for bioorthogonal labeling in living cells., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

DNA glycosylases are enzymes that initiate the base excision repair pathway, a major biochemical process that protects the genomes of all living organisms from intrinsically and environmentally inflicted damage. Recently, base excision repair inhibition proved to be a viable strategy for the therapy of tumors that have lost alternative repair pathways, such as BRCA-deficient cancers sensitive to poly(ADP-ribose)polymerase inhibition. However, drugs targeting DNA glycosylases are still in development and so far have not advanced to clinical trials. In this review, we cover the attempts to validate DNA glycosylases as suitable targets for inhibition in the pharmacological treatment of cancer, neurodegenerative diseases, chronic inflammation, bacterial and viral infections. We discuss the glycosylase inhibitors described so far and survey the advances in the assays for DNA glycosylase reactions that may be used to screen pharmacological libraries for new active compounds., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The enzyme type IIA secreted phospholipase A2 (sPLA2-IIA) is crucial for mammalian innate host defense against bacterial pathogens. Most studies have investigated the role of sPLA2-IIA in systemic bacterial infections, identifying molecular pathways of bacterial resistance against sPLA2-IIA-mediated killing, and providing insight into sPLA2-IIA mechanisms of action. Sensitization of (antibiotic-resistant) bacteria to sPLA2-IIA action by blocking bacterial resistance or by applying sPLA2-IIA to treat bacterial infections might represent a therapeutic option in the future. Because sPLA2-IIA is highly expressed at mucosal barriers, we also discuss how sPLA2-IIA is likely to be an important driver of microbiome composition; we anticipate that future research in this area may bring new insights into the role of sPLA2-IIA in health and disease., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Competing Interests: The editors declare that they have no conflicts of interest regarding the publication of this special issue.

Protein ADP-ribosylation is a reversible post-translational modification, which alters protein activity, localization, interactome or stability, leading to perturbation of cell signaling. This review summarizes the emerging data indicating that host cell ADP-ribosylating enzymes, poly(ADP-ribose) polymerases (PARPs), influence the course of a bacterial infection, in parallel to ADP-ribosylating bacterial toxins. Host cell PARP targeting could be an efficient therapeutic approach to treat certain bacterial infections, possibly by repurposing the approved or clinical trial PARP inhibitors developed for cancer therapy., (Copyright © 2019 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

As a cytoplasmic protein tyrosine kinase, Bruton's tyrosine kinase (Btk) is widely considered as a vital kinase in many aspects of different physiologic processes. It is engaged in many important signalling pathways related to the immune response, such as the B cell receptor pathway, pattern-recognition receptor pathway, and triggering receptor expressed on myeloid cell pathway. Recent studies have increasingly focused on the important role of Btk in various inflammatory diseases, which are related to Btk expression in myeloid innate immune cells, such as macrophages, dendritic cells and neutrophils. Although some investigations have explored the role of Btk in microbial infections, many aspects remain elusive, and some of the results are opposite and controversial. Considering the complicated and multiple roles of Btk in the immune system, we summarized the engagement of Btk signalling in various pathogenic microorganism infections, the possible mechanisms involved and its therapeutic potential in the control of infectious diseases., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Chronic obstructive pulmonary disease (COPD) is predominantly associated with neutrophilic inflammation. Active neutrophil elastase (NE) is a serine proteinase, secreted by neutrophils, in response to inflammation and pathogen invasion. We sought to investigate if NE could be used as a biomarker for bacterial infection in patients with COPD., Methods: NE was quantified using ProteaseTag® Active NE Immunoassay (ProAxsis, Belfast) from the sputum of COPD subjects at stable state, exacerbation and 2 weeks post treatment visit., Results: NE was measured in 90 samples from 30 COPD subjects (18 males) with a mean (range) age of 65 (45-81) years and mean (SD) FEV 1 of 47% (18). The geometric mean (95%CI) of NE at stable state was 2454 ng/mL (1460 to 4125 ng/mL). There was a significant increase in NE levels at an exacerbation (p = 0.003), and NE levels were higher in a bacterial-associated exacerbation (NE log difference 3.873, 95% CI of log difference 1.396 to 10.740, p = 0.011). NE was an accurate predictor of a bacteria-associated exacerbation (area (95%CI) under the receiver operator characteristic curve 0.812 (0.657 to 0.968)., Conclusion: NE is elevated during exacerbations of COPD. NE may be a viable biomarker for distinguishing a bacterial exacerbation in patients with COPD., Trial Registration: Leicestershire, Northamptonshire and Rutland ethics committee (reference number: 07/H0406/157).

Introduction: Urease is a nickel-containing metalloenzyme that is commonly found in different bacteria, plants, algae, and fungi and mediates the growth of many pathogenic bacteria in the acidic environment of the stomach. Despite the large number of molecules known to have excellent urease inhibitory activity, there is an alarming lack of urease inhibitor drugs on the market., Areas Covered: This review aims to provide a comprehensive overview of the different types of molecules patented as potent urease inhibitors from the year 2012 to 2018., Expert Opinion: Urease is an important target to treat urease-related bacterial infections manifesting as gastric ulcers, urinary tract infections, and kidney stones. Although many different molecules as inhibitors of urease have been reported, only a few have advanced to clinical trials. The development of new effective urease inhibitors demands new suitable lead molecules. This review covers the patents on urease inhibitors in recent years (2012-2018) with a hope to bring into focus the issue and need for availability of new urease inhibitors on the market.

Activities of MMP-2 and MMP-9 in the cytoplasm and mitochondria of kidney cells were evaluated on the models of acute renal pathologies: pyelonephritis, rhabdomyolysis, and ischemia/reperfusion of the kidney. In acute pyelonephritis, a significant increase in the level of MMP-2 and MMP-9 in kidney cells and the appearance of mitochondrial MMP-2 isoform with a lower molecular weight, but still exhibiting proteolytic activity were observed. A direct correlation between the level of MMP-2 and MMP-9 in the kidney and the severity of inflammation in pyelonephritis was revealed. Obviously, the appearance of active protease in the mitochondria of the kidney cells could have an impact on their functioning and, generally, on the fate of renal cells in this pathology.

Background: Respiratory tract infections represent a significant public health risk, and timely and accurate detection of bacterial infections facilitates rapid therapeutic intervention. Furthermore, monitoring the progression of infections after intervention enables 'course correction' in cases where initial treatments are ineffective, avoiding unnecessary drug dosing that can contribute to antibiotic resistance. However, current diagnostic and monitoring techniques rely on non-specific or slow readouts, such as radiographic imaging and sputum cultures, which fail to specifically identify bacterial infections and take several days to identify optimal antibiotic treatments., Methods: Here we describe a nanoparticle system that detects P. aeruginosa lung infections by sensing host and bacterial protease activity in vivo, and that delivers a urinary detection readout. One protease sensor is comprised of a peptide substrate for the P. aeruginosa protease LasA. A second sensor designed to detect elastases is responsive to recombinant neutrophil elastase and secreted proteases from bacterial strains., Findings: In mice infected with P. aeruginosa, nanoparticle formulations of these protease sensors-termed activity-based nanosensors (ABNs)-detect infections and monitor bacterial clearance from the lungs over time. Additionally, ABNs differentiate between appropriate and ineffective antibiotic treatments acutely, within hours after the initiation of therapy., Interpretation: These findings demonstrate how activity measurements of disease-associated proteases can provide a noninvasive window into the dynamic process of bacterial infection and resolution, offering an opportunity for detecting, monitoring, and characterizing lung infections. FUND: National Cancer Institute, National Institute of Environmental Health Sciences, National Institutes of Health, National Science Foundation Graduate Research Fellowship Program, and Howard Hughes Medical Institute., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Guanylate-binding proteins (GBPs) are conserved family of IFN-inducible GTPases that play an important role in the host immunity against bacterial, viral, and protozoan pathogens. GBPs protect the host by associating with intracellular microbes, their vacuolar niche or, in the case of viruses, with their replication complex. This association results in a restriction of the respective pathogen, yet the exact molecular mechanisms of the antimicrobial functions of GBPs are still unclear. Recent work has linked the GBPs with the activation of inflammasomes, multi-protein complexes that assemble upon recognition of pathogen- or host-derived signals and that drive the release of cytokines and host cell death. Here, we will focus on the most recent findings that have started to unravel the manifold restriction mechanism controlled by GBPs in mouse and human cells, and that shed light on the molecular cues that control GBP recruitment to bacterial membranes., (©2018 Society for Leukocyte Biology.)

Acid sphingomyelinase (ASM) is a key enzyme in sphingolipid metabolism that converts sphingomyelin to ceramide, thereby modulating membrane structures and signal transduction. Bacterial pathogens can manipulate ASM activity and function, and use host sphingolipids during multiple steps of their infection process. An increase in ceramides upon infection results in the formation of ceramide-enriched membrane platforms that serve to cluster receptor molecules and organize intracellular signaling molecules, thus facilitating bacterial uptake. In this review, we focus on how extracellular bacterial pathogens target ASM and modulate membrane properties and signaling pathways to gain entry into eukaryotic cells or induce cell death. We describe how intracellular pathogens interfere with the intralysosomal functions of ASM to favor replication and survival. In addition, bacteria utilize their own sphingomyelinases as virulence factors to modulate sphingolipid metabolism. The potential of ASM as a target for treating bacterial infections is also discussed.

Objectives: Moxifloxacin is not approved by the US Food and Drug Administration for pediatric use. Although its use might be indicated under certain conditions, data regarding its safety and tolerability in pediatric patients are limited. The primary objective of this study was to evaluate the safety of systemic moxifloxacin therapy in children., Methods: We conducted a retrospective observational study of patients aged <18 years who received oral or intravenous moxifloxacin at our institution between January 2011 and July 2016. Patient demographics, clinical characteristics, indication for moxifloxacin use, and adverse events (AEs) were extracted via chart review. The attribution of AEs to moxifloxacin use was adjudicated in consultation with a pediatric infectious disease (ID) pharmacist., Results: We identified 221 patients who received 300 courses of moxifloxacin. The average age at moxifloxacin initiation was 10.4 years. One or more AEs occurred during 195 (65%) of the courses. Of the 463 distinct AEs, 46 (9.9%) were attributed to moxifloxacin. AEs attributed to moxifloxacin included corrected QT interval (QTc) prolongation (18 [6%] courses), transaminase level elevation (7 [2.3%] courses), and increased bilirubin level (3 [1%] courses). AEs led to moxifloxacin discontinuation in 18 (6%) courses. ID consultation was associated with QTc (P < .001) and transaminase (P = .002) monitoring., Conclusions: AEs that occur during pediatric moxifloxacin therapy are relatively common but rarely serious enough to require premature discontinuation. The drug might be used safely in most children with monitoring, including evaluation for QTc prolongation, and guidance from ID specialists.

Iron is an essential nutrient for many bacteria. Since the metal is highly sequestered in host tissues, bound predominantly to heme, pathogenic bacteria often take advantage of heme uptake and degradation mechanisms to acquire iron during infection. The most common mechanism of releasing iron from heme is through oxidative degradation by heme oxygenases (HOs). In addition, an increasing number of proteins that belong to two distinct structural families have been implicated in aerobic heme catabolism. Finally, an enzyme that degrades heme anaerobically was recently uncovered, further expanding the mechanisms for bacterial heme degradation. In this analysis, we cover the spectrum and recent advances in heme degradation by infectious bacteria. We briefly explain heme oxidation by the two groups of recognized HOs to ground readers before focusing on two new types of proteins that are reported to be involved in utilization of heme iron. We discuss the structure and enzymatic function of proteins representing these groups, their biological context, and how they are regulated to provide a more complete look at their cellular role.

Pathogens have developed sophisticated strategies to evade the immune response, among which manipulation of host cellular epigenetic mechanisms plays a prominent role. In the last decade, modulation of histone acetylation in host cells has emerged as an efficient strategy of bacterial immune evasion. Virulence factors and metabolic products of pathogenic microorganisms alter expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to suppress transcription of host defense genes through epigenetic changes in histone acetylation marks. This new avenue of pathogen-host interactions is particularly important in light of introduction of HDAC inhibitors into clinical practice. Considerable effort is currently being applied to better understand the effects of HDAC inhibitors on the quality of immune responses to pathogens and to characterize the therapeutic potential of these compounds in microbial infections. In this review, we will discuss the recently discovered mechanisms utilized by bacteria to facilitate their survival within infected hosts through subversion of the host acetylation system and the effects of acetylation modulators, including HDAC inhibitors and bromodomain-containing BET protein inhibitors, on innate immune responses against microbial pathogens. Integration of these two lines of experimental evidence provides critical information on the perspectives of epigenetic therapies targeting protein acetylation in infectious diseases.

This study was aimed at demonstrating associations between peripheral biochemical parameters, endometrial leukocyte esterase (LE) and myeloperoxidase (MPO), and bacterial detection with the degree of endometrial inflammation, and determining the best time postpartum for diagnosing endometritis to predict subsequent fertility in dairy cows. Plasma albumin, blood urea nitrogen (BUN), total cholesterol (T-cho), NEFA, and BHBA concentrations were analyzed in 43 Holstein cows at 3, 5 and 7 weeks postpartum (W3, W5 and W7). Endometrial samples were collected at W3, W5 and W7 to examine LE and MPO activities, bacterial detection rates, and PMN% profiles. The 43 cows were divided into healthy (HE), subclinical endometritis (SE), and clinical endometritis (CE) groups, classified differently at W3, W5 and W7 based on the definitions of SE and CE for each of the three weeks pp. LE level had an association with PMN% in all weeks pp (P<0.05). Albumin and BUN levels had weak negative associations with endometrial PMN% at W3. Pathogenic bacterial detection rates were higher in the cows with endometritis at W3 and W5. Conception rate at first artificial insemination tended to be lower (P=0.057) in the cows diagnosed with endometritis at W3 than in the healthy cows. In conclusion, associations were found between endometrial LE and endometritis, but not for MPO and endometritis. Diagnosing endometritis in W3 may be the best moment to predict subsequent fertility.

As the most prominent clinical drug targets for the inhibition of platelet aggregation, P2Y 12 and P2Y 13 have been found to be highly expressed in both platelets and macrophages. However, the roles and function of P2Y 12/13 in the regulation of macrophage-mediated innate immune responses remain unclear. Here, we demonstrate that adenosine 5'-diphosphate (ADP), the endogenous ligand of P2Y 1 , P2Y 12 and P2Y 13 , was released both in E. coli-infected mice and from macrophages treated with either lipopolysaccharide (LPS) or Pam3CSK4. Furthermore, the expression of P2Y 13 was clearly increased in both LPS-treated macrophages and tuberculosis patients. ADP protected mice from E. coli 0111-induced peritonitis by recruiting more macrophages to the infected sites. Consistent with this, ADP and ADP-treated cell culture medium attracted more macrophages in the transwell assay by enhancing the expression of MCP-1. Nevertheless, P2Y 1 is dispensable for ADP-mediated protection against bacterial infection. However, either P2Y 12 /P2Y 13 deficiency or blocking the downstream signaling of P2Y 12 /P2Y 13 blocked the ADP-mediated immune response and allowed more bacteria to persist in the infected mice. Furthermore, extracellular signal-regulated kinase (ERK) phosphorylation was clearly increased by ADP, and this type of activation could be blocked by either forskolin or analogs of cyclic AMP (cAMP) (for example, 8-bromo-cAMP). Accordingly, ADP-induced MCP-1 production and protection against bacterial infection could also be reduced by U0126, forskolin and 8-bromo-cAMP. Overall, our study reveals a relationship between danger signals and innate immune responses, which suggests the potential therapeutic significance of ADP-mediated purinergic signaling in infectious diseases.

Apoptosis delimits platelet life span in the circulation and leads to storage lesion, which severely limits the shelf life of stored platelets. Moreover, accumulating evidence indicates that platelet apoptosis provoked by various pathological stimuli results in thrombocytopenia in many common diseases. However, little is known about how platelet apoptosis is initiated or regulated. Here, we show that PKA activity is markedly reduced in platelets aged in vitro, stored platelets, and platelets from patients with immune thrombocytopenia (ITP), diabetes, and bacterial infections. Inhibition or genetic ablation of PKA provoked intrinsic programmed platelet apoptosis in vitro and rapid platelet clearance in vivo. PKA inhibition resulted in dephosphorylation of the proapoptotic protein BAD at Ser155, resulting in sequestration of prosurvival protein BCL-XL in mitochondria and subsequent apoptosis. Notably, PKA activation protected platelets from apoptosis induced by storage or pathological stimuli and elevated peripheral platelet levels in normal mice and in a murine model of ITP. Therefore, these findings identify PKA as a homeostatic regulator of platelet apoptosis that determines platelet life span and survival. Furthermore, these results suggest that regulation of PKA activity represents a promising strategy for extending platelet shelf life and has profound implications for the treatment of platelet number-related diseases and disorders.

The flavoenzyme dihydroorotate dehydrogenase catalyzes the stereoselective oxidation of (S)-dihydroorotate to orotate in the fourth of the six conserved enzymatic reactions involved in the de novo pyrimidine biosynthetic pathway. Inhibition of pyrimidine metabolism by selectively targeting DHODHs has been exploited in the development of new therapies against cancer, immunological disorders, bacterial and viral infections, and parasitic diseases. Through a chronological narrative, this review summarizes the efforts of the scientific community to achieve our current understanding of structural and biochemical properties of DHODHs. It also attempts to describe the latest advances in medicinal chemistry for therapeutic development based on the selective inhibition of DHODH, including an overview of the experimental techniques used for ligand screening during the process of drug discovery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: This paper investigates the role of Group II Secretory Phospholipase A2 (sPLA2-IIA) as a biomarker for the diagnosis of sepsis and bacterial infection in adults. Sepsis and bacterial infection are common problems encountered by patients in the hospital and often carry adverse outcomes if not managed early., Methods: Two independent reviewers conducted a comprehensive search using Ovid MEDLINE published from years 1993 to 2016 and SCOPUS published from year 1985 to 2017 to screen for relevant studies. The main inclusion criteria included adult subjects, patients with suspected or confirmed signs of infection and relevant outcomes which looked into the role of sPLA2-IIA in detecting the presence of sepsis and bacterial infection in the subjects., Results and Discussion: Four studies met the inclusion criteria. SPLA2-IIA was found to be effective in detecting the presence of sepsis and bacterial infection in adults. The levels of serum sPLA2-IIA also correlated well with the presence of sepsis and bacterial infection., Conclusion: This systematic review highlights the role of sPLA2-IIA as a reliable tool to diagnose sepsis and bacterial infection in adult patients. Nonetheless, further studies should be done in the future to provide more compelling evidence on its application in the clinical setting.

Bacterial infections remain a major public health concern. However, broad-spectrum antibiotics largely target redundant mechanisms of bacterial survival and lead to gained resistance owing to microbial evolution. New methods are needed to attack bacterial infections, and we have only begun to seek out nature's vast arsenal of antimicrobial weapons. Enzymes offer one such weapon, and their diversity has been exploited to kill bacteria selectively through unique targets, particularly in bacterial cell walls, as well as nonselectively through generation of bactericidal molecules. In both approaches, microbial resistance has largely been absent, which bodes well for its potential use in human therapeutics. Furthermore, enzyme stabilization through conjugation to nanoscale materials and incorporation into polymeric composites enable their use on surfaces to endow them with antimicrobial properties. Here, we highlight the use of enzymes as antimicrobial agents, including applications that may prove effective in new therapeutics and through control of key societal infrastructures.

Enzymes in the α-d-phosphohexomutases superfamily catalyze the reversible conversion of phosphosugars, such as glucose 1-phosphate and glucose 6-phosphate. These reactions are fundamental to primary metabolism across the kingdoms of life and are required for a myriad of cellular processes, ranging from exopolysaccharide production to protein glycosylation. The subject of extensive mechanistic characterization during the latter half of the 20th century, these enzymes have recently benefitted from biophysical characterization, including X-ray crystallography, NMR, and hydrogen-deuterium exchange studies. This work has provided new insights into the unique catalytic mechanism of the superfamily, shed light on the molecular determinants of ligand recognition, and revealed the evolutionary conservation of conformational flexibility. Novel associations with inherited metabolic disease and the pathogenesis of bacterial infections have emerged, spurring renewed interest in the long-appreciated functional roles of these enzymes., (© 2017 Elsevier Inc. All rights reserved.)

The virulence of highly pathogenic bacteria such as Salmonella, Yersinia, Staphylococci, Clostridia, and pathogenic strains of Escherichia coli involves intimate cross-talks with the host actin cytoskeleton and its upstream regulators. A large number of virulence factors expressed by these pathogens modulate Rho GTPase activities either by mimicking cellular regulators or by catalyzing posttranslational modifications of these small proteins. This impressive convergence of virulence toward Rho GTPases and actin indeed offers pathogens the capacity to breach host defenses and invade their host, while it promotes inflammatory reactions. In return, the study of this targeting of Rho GTPases in infection has been an invaluable source of information in cell signaling, cell biology, and biomechanics, as well as in immunology. Through selected examples, I highlight the importance of recent studies on this crosstalk, which have unveiled new mechanisms of regulation of Rho GTPases; the relationship between cell shape and actin cytoskeleton organization; and the relationship between Rho GTPases and innate immune signaling.

Nanoparticles are being widely used as antibacterial agents with metal nanoparticles emerging as the most efficient antibacterial agents. There have been many studies which have reported the mechanism of antibacterial activity of nanoparticles on bacteria. In this review we aim to emphasize on all the possible mechanisms which are involved in the antibacterial activity of nanoparticles and also to understand their mode of action and role as bacterial enzyme inhibitor by comparing their antibacterial mechanism to that of antibiotics with enzyme inhibition as a major mechanism. With the emergence of widespread antibiotic resistance, nanoparticles offer a better alternative to our conventional arsenal of antibiotics. Once the biological safety of these nanoparticles is addressed, these nanoparticles can be of great medical importance in our fight against bacterial infections., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Both coagulation and fibrinolysis are tightly connected with the innate immune system. Infection and inflammation cause profound alterations in the otherwise well-controlled balance between coagulation and fibrinolysis. Many pathogenic bacteria directly exploit the host's hemostatic system to increase their virulence. Here, we review the capacity of bacteria to activate plasminogen. The resulting proteolytic activity allows them to breach tissue barriers and evade innate immune defense, thus promoting bacterial spreading. Yersinia pestis, streptococci of group A, C and G and Staphylococcus aureus produce a specific bacterial plasminogen activator. Moreover, surface plasminogen receptors play an established role in pneumococcal, borrelial and group B streptococcal infections. This review summarizes the mechanisms of bacterial activation of host plasminogen and the role of the fibrinolytic system in infections caused by these pathogens.

Caspase-1 is an inflammatory caspase that is activated through formation of inflammasome complexes in response to both pathogen-derived and endogenous mediators. The most well-known function of active caspase-1 is to cleave the proforms of inflammatory cytokines IL-1β and -18 into their active forms in response to inflammatory stimuli in immune cells. However, recent evidence suggests that caspase-1 has multiple functions in addition to this cytokine maturation role and that it is at the center of many cell responses to stress and inflammation. The current review focuses on roles for caspase-1, and the closely related caspase-11, in inflammatory forms of cell death and protein cleavage and also in protein secretion. These alternative caspase-1 functions can influence inflammatory responses, not just in immune cells but in other cell types, such as epithelia, where inflammatory cytokine production may not be a primary cell function., (© Society for Leukocyte Biology.)

An increasing resistance of pathogenic bacterial species has been considered as one of the major health problems worldwide. The discovery of novel protein targets and development of effective anti-bacterial therapeutics is of high need since for some extremely resistant pathogens we are simply left unarmed. One of new promising therapeutic strategy is the application of specific inhibitors targeting bacterial serine proteases. Pathogenic microorganisms secrete abroad range of hydrolases, including serine proteases which lead to activation of various virulence factors. Herein, we review the specific bacteria serine proteases which have an influence on pathogenicity of bacterial infection as well as we introduce the reader with a brief history of the subject.

The p110δ isoform of PI3K is known to play an important role in immunity, yet its contribution to CTL responses has not been fully elucidated. Using murine p110δ-deficient CD8(+) T cells, we demonstrated a critical role for the p110δ subunit in the generation of optimal primary and memory CD8(+) T cell responses. This was demonstrated in both acute viral and intracellular bacterial infections in mice. We show that p110δ signaling is required for CD8(+) T cell activation, proliferation and effector cytokine production. We provide evidence that the effects of p110δ signaling are mediated via Akt activation and through the regulation of TCR-activated oxidative phosphorylation and aerobic glycolysis. In light of recent clinical trials that employ drugs targeting p110δ in certain cancers and other diseases, our study suggests caution in using these drugs in patients, as they could potentially increase susceptibility to infectious diseases. These studies therefore reveal a novel and direct role for p110δ signaling in in vivo CD8(+) T cell immunity to microbial pathogens., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Objective: Aerobic vaginitis (AV) is a recently proposed term for genital tract infection in women. The diagnosis of AV is mainly based on descriptive diagnostic criteria proposed by Donders and co-workers. The objective of this study is to report AV prevalence in southwest China using an objective assay kit based on preformed enzymes and also to determine its characteristics., Materials and Methods: A total of 1948 outpatients were enrolled and tested by a commercial diagnostic kit to investigate the AV prevalence and characteristics in southwestern China. The study mainly examined the vaginal ecosystem, age distribution, Lactobacillus amount, and changes in pH. Differences within groups were analyzed by Wilcoxon two-sample test., Results: The AV detection rate is 15.40%. The AV patients were usually seen in the sexually active age group of 20-30 years, followed by those in the age group of 30-40 years. The vaginal ecosystems of all the patients studied were absolutely abnormal, and diagnosed to have a combined infection [aerobic vaginitis (AV) + bacterial vaginitis (BV) 61.33%; 184/300]. Aerobic bacteria, especially Staphylococcus aureus and Escherichia coli, were predominantly found in the vaginal samples of these women., Conclusion: AV is a common type of genital infection in southwestern China and is characterized by sexually active age and combined infection predominated by the AV and BV type., (Copyright © 2016. Published by Elsevier B.V.)

The interferon (IFN)-regulated endoribonuclease RNase-L is involved in multiple aspects of the antimicrobial innate immune response. It is the terminal component of an RNA cleavage pathway in which dsRNA induces the production of RNase-L-activating 2-5A by the 2'-5'-oligoadenylate synthetase. The active nuclease then cleaves ssRNAs, both cellular and viral, leading to downregulation of their expression and the generation of small RNAs capable of activating retinoic acid-inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome. This leads to IFNβ expression and IL-1β activation respectively, in addition to broader effects on immune cell function. RNase-L is also one of a growing number of innate immune components that interact with the cell cytoskeleton. It can bind to several cytoskeletal proteins, including filamin A, an actin-binding protein that collaborates with RNase-L to maintain the cellular barrier to viral entry. This antiviral activity is independent of catalytic function, a unique mechanism for RNase-L. We also describe here the interaction of RNase-L with the E3 ubiquitin ligase and scaffolding protein, ligand of nump protein X (LNX), a regulator of tight junction proteins. In order to better understand the significance and context of these novel binding partners in the antimicrobial response, other innate immune protein interactions with the cytoskeleton are also discussed.

During host-pathogen interactions, a complex web of events is crucial for the outcome of infection. Pathogen recognition triggers powerful cellular signaling events that is translated into the induction and maintenance of innate and adaptive host immunity against infection. In opposition, pathogens employ active mechanisms to manipulate host cell regulatory pathways toward their proliferation and survival. Among these, subversion of host cell energy metabolism by pathogens is currently recognized to play an important role in microbial growth and persistence. Extensive studies have documented the role of AMP-activated protein kinase (AMPK) signaling, a central cellular hub involved in the regulation of energy homeostasis, in host-pathogen interactions. Here, we highlight the most recent advances detailing how pathogens hijack cellular metabolism by suppressing or increasing the activity of the host energy sensor AMPK. We also address the role of lower eukaryote AMPK orthologues in the adaptive process to the host microenvironment and their contribution for pathogen survival, differentiation, and growth. Finally, we review the effects of pharmacological or genetic AMPK modulation on pathogen growth and persistence.

Background and Objective: β-Glucuronidase is a lysosomal enzyme released into the extracellular fluid during inflammation. Increased β-glucuronidase activity in the cerebrospinal and peritoneal fluid has been shown to be a useful marker of bacterial inflammation. We explored the role of β-glucuronidase in the detection of bacterial infection in bronchoalveolar lavage fluid (BALF) of paediatric patients., Methods: In this case-control study, % polymorphonuclear cell count (PMN%), β-glucuronidase activity, interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α) and elastase were measured in culture-positive (≥10(4) cfu/mL, C+) and -negative (C-) BALF samples obtained from children., Results: A total of 92 BALF samples were analysed. The median β-glucuronidase activity (measured in nanomoles of 4-methylumbelliferone (4-MU)/mL BALF/h) was 246.4 in C+ (interquartile range: 71.2-751) and 21.9 in C- (4.0-40.8) (P < 0.001). The levels of TNF-α and IL-8 were increased in C+ as compared with C- (5.4 (1.7-12.6) vs 0.7 (0.2-6.2) pg/mL, P < 0.001 and 288 (76-4300) vs 287 (89-1566) pg/mL, P = 0.042, respectively). Elastase level and PMN% did not differ significantly (50 (21-149) vs 26 (15-59) ng/mL, P = 0.051 and 20 (9-40) vs 18 (9-34) %, P = 0.674, respectively). The area under the curve of β-glucuronidase activity (0.856, 95% confidence interval (CI): 0.767-0.920) was higher than that of TNF-α (0.718; 95% CI: 0.614-0.806; P = 0.040), IL-8 (0.623; 95% CI: 0.516-0.722; P = 0.001), elastase (0.645; 95% CI: 0.514-0.761; P = 0.008) and PMN% (0.526; 95 % CI: 0.418-0.632; P < 0.001)., Conclusions: This study demonstrates a significant increase of β-glucuronidase activity in BALF of children with culture-positive bacterial inflammation. In our population β-glucuronidase activity showed superior predictive ability for bacterial lung infection than other markers of inflammation., (© 2015 Asian Pacific Society of Respirology.)

Background: FK506-binding proteins (FKBPs) contain a domain with peptidyl-prolyl-cis/trans-isomerase (PPIase) activity and bind the immunosuppressive drugs FK506 and rapamycin. FKBPs belong to the immunophilin family and are found in eukaryotes and bacteria., Scope of Review: In this review we describe two major groups of bacterial virulence-associated FKBPs, the trigger factor and Mip-like PPIases. Moreover, we discuss the contribution of host FKBPs in bacterial infection processes., Major Conclusions: Since PPIases are regarded as alternative antiinfective drug targets we highlight current research strategies utilizing pipecolinic acid and cycloheximide derivatives as well as substrate based inhibitors., General Significance: The current research strategies suggest a beneficial synergism of drug development and basic research. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Human chitotriosidase (ChT) is an active chitinase expressed by activated phagocytes. Increased ChT activity has been reported in systemic Candida albicans infections and in Gram-negative and Gram-positive bacterial infections, indicating that an increase in ChT activity reflects phagocyte activation. The aim of this study was to determine the changes in serum ChT activity in patients who underwent high dose chemotherapy (HDC) and stem cell transplantation (SCT), who are at an increased risk for fungal and bacterial infections due to depression of the immune system during the neutropenic period., Patients and Methods: A total of 55 SCT patients were included in the study. Serum ChT activity was determined before the initiation of HDC and during the neutropenic period after hematopoietic stem cell reinfusion on post-transplant first, fifth and tenth days., Results: Chitotriosidase levels before transplantation were significantly lower than the results at first, fifth and tenth days post-hematopoietic stem cell reinfusion., Conclusions: Although the number of neutrophils was low, ChT enzyme activity was high in newly produced granules of neutrophils. Chitotriosidase may be supplemented as a drug for preventing and treating infections in the near future.

Cytochrome bd is a terminal quinol oxidase of the bacterial respiratory chain. This tri-heme integral membrane protein generates a proton motive force at lower efficiency than heme-copper oxidases. This notwithstanding, under unfavorable growth conditions bacteria often use cytochrome bd in place of heme-copper enzymes as the main terminal oxidase. This is the case for several pathogenic and opportunistic bacteria during host colonization. This review summarizes recent data on the contribution of cytochrome bd to bacterial resistance to hydrogen peroxide, nitric oxide, and peroxynitrite, harmful species produced by the host as part of the immune response to microbial infections. Growing evidence supports the hypothesis that bd-type oxidases contribute to bacterial virulence by promoting microbial survival under oxidative and nitrosative stress conditions. For these reasons, cytochrome bd represents a protein target for the development of next-generation antimicrobials.

Caspase cysteine proteases are factors widely recognized for their role in the induction of apoptotic cell death. Caspases induce apoptosis during the inflammatory response to pathogen infection; in addition, caspases such as caspase-1 and caspase-11 are known to be involved in the production of inflammatory cytokines in response to bacterial infections. Caspase-1 is activated in the inflammasome, an intracellular protein complex that is formed by the recognition of intracellular ligands or cellular stresses by sensor molecules such as NOD-like receptors. Under certain conditions, caspase-11 is required for the activation of the caspase-1 inflammasome, referred to as the non-canonical inflammasome. In addition to these caspases, accumulating evidence indicates that caspase-8 also contributes to the production of inflammatory cytokines. In contrast to caspase-1, caspase-8 is activated by receptors located on the plasma membrane including dectin-1, TLR-3/4, and Fas. Recently, Fas-mediated caspase-8 activation and inflammatory cytokine production have been shown to play a significant role in the regulation of bacterial infections. This review highlights the functional roles and activation mechanisms of caspase-1/-11 in innate immune responses against bacterial infection. In addition, we discuss the novel aspects of caspase-8 function in comparison with caspase-1/-11 during innate inflammatory responses.

Introduction: The carbonic anhydrases (CAs, EC 4.2.1.1), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, as well as in the growth and virulence of pathogens belonging to bacteria, fungi and protozoa., Areas Covered: CAs belonging to at least four genetic families, the α-, β-, γ- and η-CAs, were discovered and characterized in many pathogens: i) Bacteria encode enzymes from one or more such families, which were investigated as potential drug targets. Inhibition of bacterial CAs by sulfonamides/phenol derivatives lead to inhibition of growth of the pathogen for Helicobacter pylori, Mycobacterium tuberculosis, Brucella suis; ii) Fungi encode for α- and β-CAs, and inhibitors of the sulfonamide, thiol or dithiocarbamate type inhibited the growth of some of them (Malassezia globosa, Candida albicans, Crytpococcus neoformans, etc) in vivo; and iii) Protozoa encode α-, β- or η-CAs. Sulfonamide, thiols and hydroxamates effectively killed such parasites (Trypanosoma cruzi, Leishmania donovani chagasi, Plasmodium falciparum) in vivo., Expert Opinion: None of the microorganism CAs is validated as drug targets as yet, but the inhibitors designed against many such enzymes showed interesting in vitro/in vivo results. By interfering with the activity of CAs from microorganisms, both pH homeostasis as well as crucial biosynthetic reactions are impaired, which lead to significant antiinfective effects, not yet exploited for obtaining pharmacological agents. As resistance to the clinically used antiinfectives is a serious healthcare problem worldwide, inhibition of parasite CAs may constitute an alternative approach for obtaining such agents with novel mechanisms of action.

The non-mevalonate or 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway is responsible for generating isoprenoid precursors in plants, protozoa, and bacteria. Because this pathway is absent in humans, its enzymes represent potential targets for the development of herbicides and antibiotics. 1-Deoxy-d-xylulose (DXP) reductoisomerase (DXR) is a particularly attractive target that catalyzes the pathway's first committed step: the sequential isomerization and NADPH-dependent reduction of DXP to MEP. This article provides a comprehensive review of the mechanistic and structural investigations on DXR, including its discovery and validation as a drug target, elucidation of its chemical and kinetic mechanisms, characterization of inhibition by the natural antibiotic fosmidomycin, and identification of structural features that provide the molecular basis for inhibition of and catalysis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Whey acidic proteins (WAP) belong to a large gene family of antibacterial peptides that perform critical immune system functions. The function of human epididymis protein 4 (HE4), a 124-amino acid long polypeptide that has two whey acidic protein four-disulfide core (WFDC) domains, is not well studied. Here, a fusion gene encoding the HE4 protein fused to an IgG1 Fc domain was constructed. The recombinant HE4 protein was expressed as a secretory protein in Pichia pastoris and mammalian HEK293-F cells and was subsequently purified. Our data suggested that the HE4 protein produced by these two expression systems bound to both gram-negative and gram-positive bacteria, but demonstrated slightly inhibitory activity towards the growth of Staphylococcus aureus. Moreover, HE4 exhibited proteinase inhibitory activity towards trypsin, elastase, matrix metallopeptidase 9, and the secretory proteinases from Bacillus subtilis. The effects of glycosylation on the biochemical characterization of HE4 were also investigated. LC-ESI-MS glycosylation analysis showed that the high-mannose glycosylated form of HE4 expressed by P. pastoris has lower biological activity when compared to its complex-glycosylated form produced from HEK293-F cells. The implications of this are discussed, which may be provide theoretical basis for its important role in the development of cancer and innate immune system., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In bacterial pathogenesis, monitoring and adapting to the dynamically changing environment in the host and an ability to disrupt host immune responses are critical. The virulence determinants of pathogenic bacteria include the sensor/signaling proteins of the serine/threonine protein kinase (STPK) family that have a dual role of sensing the environment and subverting specific host defense processes. STPKs can sense a wide range of signals and coordinate multiple cellular processes to mount an appropriate response. Here, we review some of the well studied bacterial STPKs that are essential virulence factors and that modify global host responses during infection.

Components of fatty acid biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Compounds of series A (4a-4 g) and series B (5a-5 g) were synthesized by the formation of an amine bond between aromatic acid and 4-phenylthiazol-2-amine or 4-(4-bromophenyl)thiazol-2-amine. These thiazole derivatives have evaluated as potent FabH inhibitors. Nineteen compounds (4b-4h, 4 k, 4 l, 5a-5h, 5k, 5l) are reported for the first time. Most of the synthesized compounds exhibited antibacterial activity in the MTT assay. The MIC value of these compounds ranged from 1.56 μg/mL to 100 μg/mL. Moreover, the tested compounds also showed FabH inhibition ability with IC50 value ranging from 5.8 μM to 48.1 μM. The IC50 values are near the MIC values. Compound 5f has exhibited the best antibacterial and Escherichia coli FabH inhibitory activity. Docking simulation and the QSAR study was conducted for learning about binding mode and the relationship between structure and activity., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Polymorphonuclear leukocytes (PMNs) are essential for the human innate immune defense, limiting expansion of invading microorganisms. PMN turnover is controlled by apoptosis, but the regulating signaling pathways remain elusive, largely due to inherent differences between mice and humans that undermine use of mouse models for understanding human PMN biology. Here, we aim to elucidate signal transduction mediating survival of human peripheral blood PMNs in response to bacteria, such as Yersinia pseudotuberculosis, an enteropathogen that causes the gastro-intestinal disease yersiniosis, as well as Escherichia coli and Staphylococcus aureus. Determinations of cell death reveal that uninfected control cells undergo apoptosis, while PMNs infected with either Gram-positive or -negative bacteria show profoundly increased survival. Infected cells exhibit decreased caspase 3 and 8 activities, increased mitochondrial integrity and are resistant to apoptosis induced by a death receptor ligand. This bacteria-induced response is accompanied by pro-inflammatory cytokine production including interleukin-8 and tumor necrosis factor-α competent to attract additional PMNs. Using agonists and pharmacological inhibitors, we show participation of Toll-like receptor 2 and 4, and interestingly, that protein kinase C (PKC) and phosphatidylcholine-specific phospholipase C (PC-PLC), but not tyrosine kinases or phosphatidylinositol-specific phospholipase C (PI-PLC) are key players in this dual PMN response. Our findings indicate the importance of prolonged PMN survival in response to bacteria, where general signaling pathways ensure complete exploitation of PMN anti-microbial capacity.