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Objective: Patients with multi-vessel coronary artery disease (MVD) compared to single-vessel coronary artery disease (CAD) have more comorbidities and poor in-hospital outcomes. We aim to analyze MVD-AMI patients regarding clinical data and short-term outcomes. Methods: This is a retrospective analysis of the prospectively collected data registry, a single-center study reviewing the clinical details and hospital outcome measures of AMI patients referred to our center for early revascularization from 2016 to 2019. Result: Out of 3041 patients presented with AMI, 491 (16%) had MVD on coronary angiogram. MVD-AMI patients were older, had a higher prevalence of DM, HTN, and prior history of ischemic heart disease compared to the non- MVD -AMI group (p

Background: Mazaryun (Daphne oleoides Schreb.) is used as an anti-inflammatory drug in Unani medicine after detoxification, as it is defined under fourth-degree drugs. Objective(s): To evaluate and compare the anti-inflammatory activity of crude and detoxified Mazaryun in maximum and minimum doses. Materials and methods: Anti-inflammatory activity was carried out by carrageenan-induced paw edema test. Wistar rats of either sex, weighing 150–200 gm, were divided into seven groups (I, II, IIIA, IIIB, IVA, IVB, and V) of six animals in each. Group I - plain control, administered with 1 ml of 1% CarboxyMethyl Cellulose (CMC); Group II - standard control, given Diclofenac Sodium (6 mg/kg); Group III - crude Mazaryun and Group IV - detoxified Mazaryun, A and B are maximum and minimum doses of test drug, respectively; and V group - positive control was not treated with any other drugs. The data was statistically analyzed by ANOVA repeated for inter-group analysis and ANOVA one-way for intra-group analysis with post hoc Tukey Kramer multiple comparison test. The GC–MS analysis of crude and detoxified leaves of Mazaryun was also carried out in continuation of study to determine the phytochemical changes before and after detoxification. Results: Maximum dose of detoxified Mazaryun and standard control groups showed significant anti–inflammatory activity at p

Abstract Background Shortening of the hospital stay in patients admitted with the diagnosis of acute myocardial infarction (AMI) has been observed within the last decades. Our center is the only cardiac center in the region providing tertiary care facility and hence receives all AMI patients deemed suitable for invasive assessment and management and this leads to huge required demand. Our aim is to assess feasibility and safety of the early discharge of selected proportion of AMI patients. Result Out of 557 of patients presented with AMI and treated with percutaneous coronary intervention (PCI), 310 (56%) were discharged early. Men patients and pilgrims were more prevalent among the early discharge group. Early discharged patients had significantly less comorbidities compared to the other group of patients. Moreover, they presented mainly with ST-elevation myocardial infarction (P = 0.04) and treated more with primary percutaneous coronary intervention (PPCI) (P = 0.04). They had favorable coronary anatomy (P = 0.01 and 0.02 for left main and multi-vessel coronary artery disease, respectively), better hospital course, and higher left ventricular ejection fraction compared to non-early discharged patients (P = 0.006 and

Abstract Background Acute myocardial infarction (AMI) is usually caused by rupture of an atherosclerotic plaque leading to thrombotic occlusion of a coronary artery. Cardiovascular disease has recently emerged as the leading cause of death during hajj. Our aim is to demonstrate the AMI pilgrim’s related disparities and comparing them to non-pilgrim patients. Result Out of 3044 of patients presented with AMI from January 2016 to August 2019, 1008 (33%) were pilgrims. They were older in age (P < 0.001) and showed significantly lower rates cardiovascular risk factors (P < 0.001 for DM, smoking, and obesity). Pilgrims were also less likely to receive thrombolytic therapy (P < 0.001), show lower rate of late AMI presentation (P < 0.001), develop more LV dysfunction post AMI (P < 0.001), and have critical CAD anatomy in their coronary angiography (P < 0.001 for MVD and = 0.02 for LM disease) compared to non-pilgrim AMI patients. Despite AMI pilgrims recorded higher rate of primary percutaneous coronary intervention (PPCI) procedures, they still showed poor hospital outcomes (P < 0.001, 0.004, < 0.001, 0.05, and 0.001, respectively for pulmonary edema, cardiogenic shock, mechanical ventilation, cardiac arrest, and in-hospital mortality, respectively). Being a pilgrim and presence of significant left ventricular systolic dysfunction, post AMI was the two independent predictors of mortality among our studied patients (P = 0.005 and 0.001, respectively). Conclusion Although AMI pilgrims had less cardiovascular risk factors and they were early revascularized, they showed higher rates of post myocardial infarction complication and poor hospital outcomes. Implementation of pre-hajj screening, awareness and education programs, and primary and secondary preventive measures should be taken in to consideration to improve AMI pilgrim’s outcome.

Sammulfar (arsenic trioxide) is a notorious poison and has extensively been studied for its toxicity. It is in use for various purposes for centuries and is used even today as a therapeutic agent in the form of kushta (calx) in traditional systems of medicine, particularly Unani medicine, but without apparent safety data. The present study, therefore, was conducted to produce data for prolong use of calx of arsenic trioxide. The calx (test drug) was prepared by the method described in National Formulary of Unani Medicine. The study was carried in healthy Wistar rats of either sex; weighing 150-250 g; 2-3 months of age, in a dose dependent manner, following the methods of Gupta et al. (2002), Ghosh (2008) and Klaassan (2008). The animals were divided into four groups of 10 animals each. Group I served as control, where as group II, III and IV were used for three dose levels of the test drug i.e. low (8.75 mg–1 kg), medium (17.50 mg–1 kg) and higher (26.25 mg–1 kg). Standard parameters usually applied for chronic toxicity studies were considered. The study revealed dose dependent toxicity. Usual signs of chronic toxicity were observed during the study. Low dose of Kushta Sammulfar (KSF) did not produce remarkable toxic effects. Mild to moderate toxicity was seen in KSF-II and KSF-III.

Liver cancer is globally the most frequent fatal malignancy, and its identification is critical for making clinical decisions about treatment options. Pathological diagnostics and contemporary imaging technologies provide insufficient information for tumor identification. Hydrogen peroxide (H 2 O 2 ), an emerging biomarker is a powerful oxidant found in the tumor microenvironment, and stimulates the invasion, proliferation, and metastasis of liver cancer cells. This study describes a medically effective and sensitive electrochemical sensor based on ascorbic acid immobilized zinc selenide nanoparticles (AsA@Zn-Se NPs) decorated on a glassy carbon electrode (GCE) for determining H 2 O 2 in PBS and human serum samples of liver cancer patients. The morphological and structural characterization of fabricated sensor is done by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), ultraviolet-visible (UV-Vis) spectroscopy, energy dispersive X-ray (EDX), and scanning electron microscopy (SEM). Ascorbic acid (AsA), an antioxidant for H 2 O 2 redox behavior, is immobilized on Zn-Se NPs to aid H 2 O 2 detection through cyclic voltammetry (CV). The sensor exhibits a low detection limit, and board linear range of 0.49 µM and 0-70 µM, respectively. The low-cost electrochemical sensor is robust for up to 100 cycles. Elecys AFP assay results validate that increasing alpha-fetoprotein (AFP) concentration, a biomarker for liver cancer, can increase the H 2 O 2 levels in serum samples. Therefore, the proposed sensor can be used to diagnose liver cancer in clinical settings., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The UDP-3- O -( R -3-hydroxyacyl)- N -acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting antibiotics toward clinical therapeutics has been hindered by the limited antibiotic profile of reported non-hydroxamate inhibitors and unexpected cardiovascular toxicity observed in certain hydroxamate and non-hydroxamate-based inhibitors. Here, we report the preclinical characterization of a slow, tight-binding LpxC inhibitor, LPC-233, with low picomolar affinity. The compound is a rapid bactericidal antibiotic, unaffected by established resistance mechanisms to commercial antibiotics, and displays outstanding activity against a wide range of Gram-negative clinical isolates in vitro. It is orally bioavailable and efficiently eliminates infections caused by susceptible and multidrug-resistant Gram-negative bacterial pathogens in murine soft tissue, sepsis, and urinary tract infection models. It displays exceptional in vitro and in vivo safety profiles, with no detectable adverse cardiovascular toxicity in dogs at 100 milligrams per kilogram. These results establish the feasibility of developing oral LpxC-targeting antibiotics for clinical applications.

Background: In the case of COVID-19 patients, it has been observed that the immune system of the infected person exhibits an extreme inflammatory response known as cytokine release syndrome (CRS) where the inflammatory cytokines are swiftly produced in quite large amounts in response to infective stimuli. Numerous case studies of COVID-19 patients with severe symptoms have documented the presence of higher plasma concentrations of human interleukin-6 (IL-6), which suggests that IL-6 is a crucial factor in the pathophysiology of the disease. In order to prevent CRS in COVID-19 patients, the drugs that can exhibit binding interactions with IL-6 and block the signaling pathways to decrease the IL-6 activity may be repurposed., Methods: This research work focused on molecular docking-based screening of the drugs celecoxib (CXB) and dexamethasone (DME) to explore their potential to interact with the binding sites of IL-6 protein and reduce the hyper-activation of IL-6 in the infected personnel., Results: Both of the drugs were observed to bind with the IL-6 (IL-6 receptor alpha chain) and IL-6Rα receptor with the respective affinities of -7.3 kcal/mol and -6.3 kcal/mol, respectively, for CXB and DME. Moreover, various types of binding interactions of the drugs with the target proteins were also observed in the docking studies. The dynamic behaviors of IL-6/IL-6Rα in complex with the drugs were also explored through molecular dynamics simulation analysis. The results indicated significant stabilities of the acquired drug-protein complexes up to 100 ns., Conclusion: The findings of this study have suggested the potential of the drugs studied to be utilized as antagonists for countering CRS in COVID-19 ailment. This study presents the studied drugs as promising candidates both for the clinical and pre-clinical treatment of COVID-19., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In recent years, the growing research interests in the applications of plant and fruit extracts (synthetic/stabilization materials for the nanomaterials, medicinal applications, functional foods, and nutraceuticals) have led to the development of new analytical techniques to be utilized for identifying numerous properties of these extracts. One of the main properties essential for the applicability of these plant extracts is the antioxidant capacity (AOC) that is conventionally determined by spectrophotometric techniques. Nowadays, electrochemical methodologies are emerging as alternative tools for quantifying this particular property of the extract. These methodologies address numerous drawbacks of the conventional spectroscopic approach, such as the utilization of expensive and hazardous solvents, extensive sample pre-treatment requirements, long reaction times, low sensitivity, etc. The electrochemical methodologies discussed in this review include cyclic voltammetry (CV), square wave voltammetry (SWV), differential pulse voltammetry (DPV), and chronoamperometry (CAP). This review presents a critical comparison between both the conventional and electrochemical approaches for the quantification of the parameter of AOC and discusses the numerous applications of the obtained bioextracts based on the AOC parameter.

Surfactant stabilized Gold (Au) nanomaterials (NMs) have been documented extensively in recent years for numerous sensing applications in the academic literature. Despite the crucial role these surfactants play in the sensing applications, the comprehensive reviews that highlights the fundamentals associated with these assemblies and impact of these surfactants on the properties and sensing mechanisms are still quite scare. This review is an attempt in organizing the vast literature associated with this domain by providing critical insights into the fundamentals, preparation methodologies and sensing mechanisms of these surfactant stabilized Au NMs. For the simplification, the surfactants are divided into the typical and advanced surfactants and the Au NMs are classified into Au nanoparticles (NPs) and Au nanoclusters (NCs) depending upon the complexity in structure and size of the NMs respectively. The preparative methodologies are also elaborated for enhancing the understanding of the readers regarding such assemblies. The case studies regarding surfactant stabilized Au NMs were further divided into colorimetric sensors, surface plasmonic resonance (SPR) based sensors, luminescence-based sensors, and electrochemical/electrical sensors depending upon the property utilized by the sensor for the sensing of an analyte. Future perspectives are also discussed in detail for the researchers looking for further progress in that particular research domain., (Copyright © 2021 Elsevier Inc. All rights reserved.)

SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, can neutralize the virus. It is, however, unknown which features of the serological response may affect clinical outcomes of COVID-19 patients. We analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Within this cohort, 25 patients died of their illness. Higher ratios of IgG antibodies targeting S1 or RBD domains of spike compared to nucleocapsid antigen were seen in outpatients who had mild illness versus severely ill patients. Plasma antibody increases correlated with decreases in viral RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes. Pseudovirus neutralization assays and a scalable ELISA measuring antibodies blocking RBD-ACE2 interaction were well correlated with patient IgG titers to RBD. Outpatient and asymptomatic individuals' SARS-CoV-2 antibodies, including IgG, progressively decreased during observation up to five months post-infection., (Copyright © 2020, American Association for the Advancement of Science.)

B cells are critical for the production of antibodies and protective immunity to viruses. Here we show that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) display early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify convergence of antibody sequences across SARS-CoV-2-infected patients, highlighting stereotyped naive responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and SARS-CoV., Competing Interests: Declaration of Interests A.T.S. is a scientific founder of Immunai and receives research funding from Arsenal Biosciences not related to this study. M.H. is an employee of ATUM. S.D.B. has consulted for Regeneron, Sanofi, and Novartis on topics unrelated to this study. S.D.B., K.R., P.S.K., and A.E.P. have filed provisional patent applications related to serological tests for SARS-CoV-2 antibodies. K.C.N. reports grants from National Institute of Allergy and Infectious Diseases (NIAID), Food Allergy Research & Education (FARE), and End Allergies Together (EAT); National Heart, Lung, and Blood Institute (NHLBI), and National Institute of Environmental Health Sciences (NIEHS), and is the director of FARE and World Allergy Organization (WAO) Center of Excellence at Stanford; advisor at Cour Pharma; co-founder of Before Brands, Alladapt, Latitude, and IgGenix; National Scientific Committee member at Immune Tolerance Network (ITN) and National Institutes of Health (NIH); a recipient of a Research Sponsorship from Nestle; Consultant and Advisory Board Member at Before Brands, Alladapt, Iggenix, NHLBI, and Probio; Data and Safety Monitoring Board member at NHLBI; and has US patents for basophil testing, multifood immunotherapy and prevention, monoclonal antibodies from plasmablasts, and devices for diagnostics. The remaining authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, could offer protective immunity, and may affect clinical outcomes of COVID-19 patients. We analyzed 625 serial plasma samples from 40 hospitalized COVID-19 patients and 170 SARS-CoV-2-infected outpatients and asymptomatic individuals. Severely ill patients developed significantly higher SARS-CoV-2-specific antibody responses than outpatients and asymptomatic individuals. The development of plasma antibodies was correlated with decreases in viral RNAemia, consistent with potential humoral immune clearance of virus. Using a novel competition ELISA, we detected antibodies blocking RBD-ACE2 interactions in 68% of inpatients and 40% of outpatients tested. Cross-reactive antibodies recognizing SARS-CoV RBD were found almost exclusively in hospitalized patients. Outpatient and asymptomatic individuals' serological responses to SARS-CoV-2 decreased within 2 months, suggesting that humoral protection may be short-lived., Competing Interests: Competing interests: The authors declare no competing interests.

Extraction of toxic heavy metal ions from aqueous medium using poly(N-isopropylmethacrylamide-acrylic acid) (P(NiPmA-Ac)) microgels as adsorbent has been investigated in present study. P(NiPmA-Ac) microgel particles were prepared by free radical precipitation polymerization in aqueous medium. Morphology and size of the prepared microgel particles was investigated by transmission electron microscopy (TEM). The Fourier transform infrared (FT-IR) analysis of pure and metal ion-loaded microgel particles was performed to confirm the presence of various functionalities of microgel particles and their interaction with metal ions extracted from aqueous medium. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to investigate the thermal stability and thermal behavior of pure and metal ion-loaded microgel particles. Contents of metal ions loaded into microgel particles were determined by TGA analysis. It was observed that P(NiPmA-Ac) particles have a potential to extract Cu 2+ and Co 2+ ions from aqueous medium. The Freundlich adsorption isotherm model best interprets the adsorption process as compared with the Langmuir model. Value of R 2 according to the Freundlich adsorption isotherm was found to be 0.994 and 0.993 for Cu 2+ and Co 2+ ions, respectively. Adsorption process was followed by pseudo second order kinetics for Cu 2+ and Co 2+ ions with R 2 values of 0.999 for both metal ions. Thermodynamic study showed that adsorption process was spontaneous, feasible, and endothermic in nature. Entropy was decreased at adsorbate-adsorbent interface during adsorption process. Adsorbent was recycled and reused for removal of Cu 2+ ions, and adsorption efficiency was found to be maintained up to three cycles. Microgel particles also have ability to extract Cu 2+ ions efficiently from electroplating wastewater. Graphical abstract.

Conversion of nitroaniline (NA), a highly toxic pollutant that has been released into aquatic systems due to unmanaged industrial development in recent years, into the less harmful or a useful counterpart is the need of the hour. Various methods for its conversion and removal have been explored. Owing to its nominal features of advanced effectiveness, the chemical reduction of 4-NA using various different nanocatalytic systems is one such approach that has attracted tremendous interest over the past few years. The academic literature has been confined to case studies involving silver (Ag) and gold (Au) nanoparticles, as these are the two most widely used materials for the synthesis of nanocatalytic assemblies. Focus has also been given to sodium borohydride (NaBH 4 ), which is used as a reductant during the chemical reduction of NA. This systematic review summarizes the fundamentals associated with the catalytic degradation of 4-NA, and presents a comprehensive and critical study of the latest modifications used in the synthesis of these catalytic systems. In addition, the kinetics, mechanisms, thermodynamics, as well as the future directions required for understanding this model reaction, have been provided in this particular study., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Potential hazardous effects caused by non-biodegradable plastics are considered to be one of the most widely discussed and notable challenges of the 21st century. To address this particular problem, immense efforts have been devoted to the preparation of biodegradable plastics material. This green approach mitigates the major drawbacks e.g. improper waste management, low degradation rates, waste accumulation in water reservoirs and harmful chemical reagents hence providing a natural, economical and biodegradable alternative to the customarily employed non-biodegradable plastics. This review provides an insight into recently engineered biodegradable plastics used for packaging applications. Properties such as barrier/permeation indexes, thermal, electrical and mechanical characteristics of the biodegradable plastics are considered in detail for developing an understanding regarding the fundamentals of biodegradable materials. Recent literature (2010-2018) was classified according to the composition and nature of the used material. Materials such as polylactic acid, polyhydroxyalkanoates, polyhydroxybutyrate, polycaprolactone, starch and cellulose were comprehensively discussed along with their properties and blending agents.

In this study, zinc ferrite nanoparticles (ZF-NPs) were synthesized using aqueous seed extract of Piper nigrum as a bio-reducing and stabilizing agent. FTIR, SEM, FE-SEM, XRD, and TGA have been used for characterizing ZF-NPs. The results showed that Piper nigrum stabilized ZF-NPs have high purity and size range of 60-80 nm. The performance of the ZF-NPs has been investigated by photocatalytic reduction of methylene blue (MB) in the presence of sunlight. The factors responsible for affecting the degradation values of the reaction were also explored for developing a better understanding of the phenomenon.

Nitrophenol is common carcinogenic pollutant known for its adverse effects on human beings and aquatic life. During the last few decades, the chemical reduction of nitrophenol compounds has been widely reported as the advanced removal methodology for such hazardous dyes from aqueous reservoirs. Many researchers have utilized different nanocatalytic systems using sodium borohydride (NaBH 4 ) as the reducing agent for acquiring industrially useful reduction product of aminophenol by carrying out the chemical reduction of nitrophenols. Polymeric material supported monometallic nanoparticles are widely reported catalyst for the degradation of 2-nitrophenol (2-NP) and 4-nitrophenol (4-NP). This review critically discusses the pros and cons of numerous supporting mediums of nanocatalytic assemblies used for the immobilization of nanomaterials. Mechanism and kinetic analysis of the reduction reaction of 2-NP and 4-NP have also been explained in this study. In addition, recent literature has also been effectively summarized in the tabular form for developing a better understanding of the reader. Pictorial representation of key nanocatalytic assemblies and catalytic reduction mechanism has also been narrated in this study.

Intrinsic and acquired drug resistance and induction of secondary malignancies limit successful chemotherapy. Because mutagenic translesion synthesis (TLS) contributes to chemoresistance as well as treatment-induced mutations, targeting TLS is an attractive avenue for improving chemotherapeutics. However, development of small molecules with high specificity and in vivo efficacy for mutagenic TLS has been challenging. Here, we report the discovery of a small-molecule inhibitor, JH-RE-06, that disrupts mutagenic TLS by preventing recruitment of mutagenic POL ζ. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL ζ. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL ζ recruitment. JH-RE-06 inhibits mutagenic TLS and enhances cisplatin-induced toxicity in cultured human and mouse cell lines. Co-administration of JH-RE-06 with cisplatin suppresses the growth of xenograft human melanomas in mice, establishing a framework for developing TLS inhibitors as a novel class of chemotherapy adjuvants., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This review is based on the adsorption characteristics of sorghum (Sorghum bicolor) for removal of heavy metals from aqueous media. Different parameters like pH, temperature of the medium, sorghum concentration, sorghum particle size, contact time, stirring speed and heavy metal concentration control the adsorption efficiency of sorghum biomass for heavy metal ions. Sorghum biomass showed maximum efficiency for removal of heavy metal ions in the pH range of 5 to 6. It is an agricultural waste and is regarded as the cheapest biosorbent, having high adsorption capacity for heavy metals as compared to other reported adsorbents, for the treatment of heavy metal polluted wastewater. Adsorption of heavy metal ions onto sorghum biomass follows pseudo second order kinetics. Best fitted adsorption isotherm models for removal of heavy metal ions on sorghum biomass are Langmuir and Freundlich adsorption isotherm models. Thermodynamic aspects of heavy metal ions adsorption onto sorghum biomass have also been elaborated in this review article. How adsorption efficiency of sorghum biomass can be improved by different physical and chemical treatments in future has also been elaborated. This review article will be highly useful for researchers working in the field of water treatment via biosorption processing. The quantitative demonstrated efficiency of sorghum biomass for various heavy metal ions has also been highlighted in different sections of this review article.

The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains., (Copyright © 2017 Lemaître et al.)

Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.

The LpxC enzyme in the lipid A biosynthetic pathway is one of the most promising and clinically unexploited antibiotic targets for treatment of multidrug-resistant Gram-negative infections. Progress in medicinal chemistry has led to the discovery of potent LpxC inhibitors with a variety of chemical scaffolds and distinct antibiotic profiles. The vast majority of these compounds, including the nanomolar inhibitors L-161,240 and BB-78485, are highly effective in suppressing the activity of Escherichia coli LpxC (EcLpxC) but not divergent orthologs such as Pseudomonas aeruginosa LpxC (PaLpxC) in vitro. The molecular basis for such promiscuous inhibition of EcLpxC has remained poorly understood. Here, we report the crystal structure of EcLpxC bound to L-161,240, providing the first molecular insight into L-161,240 inhibition. Additionally, structural analysis of the EcLpxC/L-161,240 complex together with the EcLpxC/BB-78485 complex reveals an unexpected backbone flipping of the Insert I βa-βb loop in EcLpxC in comparison with previously reported crystal structures of EcLpxC complexes with l-threonyl-hydroxamate-based broad-spectrum inhibitors. Such a conformational switch, which has only been observed in EcLpxC but not in divergent orthologs such as PaLpxC, results in expansion of the active site of EcLpxC, enabling it to accommodate LpxC inhibitors with a variety of head groups, including compounds containing single (R- or S-enantiomers) or double substitutions at the neighboring Cα atom of the hydroxamate warhead group. These results highlight the importance of understanding inherent conformational plasticity of target proteins in lead optimization.