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The incidences of methicillin-resistant strains of Staphylococcus aureus (MRSA) and their survival inside the macrophages are the major attributes of the relapsed infections after antimicrobial therapy, and it is a global problem. In this context, we have previously demonstrated 4-methoxy-1-methyl-2-oxopyridine-3-carbamide (MMOXC), a Ricinine derivative exhibiting anti-S. aureus and anti-biofilm characteristics by competitively inhibiting uridine monophosphate kinase (UMPK), UDP-N-acetyl muramyl pentapeptide ligase (Mur-F), and peptidyl deformylase, (PDF). In the present study, the stability of this competitive inhibitor MMOXC was evaluated by showing its ability to remain bound to the active sites of UMPK, Mur-F, and PDF even after increasing the incubation time, temperature, pH, and substrate concentration. On growing MRSA in fewer concentrations of MMOXC, these strains could not attain resistance to MMOXC and at the same time distinct reductions in the expression of UMPK, Mur-F, and PDF genes were noted. In vitro, infective models were generated by infecting MRSA to RAW 264.7 and human monocyte-derived macrophage (hMDM) cell lines. In these infected cell lines, in spite of increased nitric oxide synthase (NOS), NADPH–P450 reductase, superoxide dismutase, catalase, and peroxidase activities, the MRSA survived. At 640 µM/ml, the concentration of MMOXC penetrated into these infected cells and obliterated MRSA. While treating uninfected macrophage cell lines with MMOXC, no appreciable effect was observed indicating that MMOXC is the most suitable drug for the treatment of infections caused by MRSA. [ABSTRACT FROM AUTHOR]

A series of heterocyclic ring-fused analogs of 20(S)-protopanaxadiol (PPD) were synthesized and their antibacterial activities against Staphylococcus aureus Newman strain and multidrug-resistant strains (USA300, NRS-1, NRS-70, NRS-100, NRS-108, NRS-271, XJ017, and XJ036) were evaluated. [Display omitted] • Multidrug-resistant bacterial infections are becoming a life-threatening issue. • 20(S)-Protopanaxadiol derivatives were synthesized based on the hit compound. • Most derivatives exhibited moderate to potent antibacterial activities. Multidrug-resistant (MDR) bacterial infections are becoming a life-threatening issue in public health; therefore, it is urgent to develop novel antibacterial agents for treating infections caused by MDR bacteria. The 20(S)-protopanaxadiol (PPD) derivative 9 was identified as a novel antibacterial hit compound in screening of our small synthetic natural product-like (NPL) library. A series of novel PPD derivatives with heterocyclic rings fused at the C-2 and C-3 positions of the A-ring were synthesized and their antibacterial activities against Staphylococcus aureus (S. aureus) Newman strain and MDR S. aureus strains (USA300, NRS-1, NRS-70, NRS-100, NRS-108, NRS-271, XJ017, and XJ036) were evaluated. Among these compounds, quinoxaline derivative 56 (SH617) exhibited the highest activity with MICs of 0.5–4 μg/mL against the S. aureus Newman strain and the eight MDR S. aureus strains. Its antibacterial activity was comparable to that of the positive control, vancomycin. In the zebrafish, 56 revealed no obvious toxicity even at a high administered dose. In vivo , following a lethal infection induced by USA300 strains in zebrafish, 56 exhibited significantly increased survival rates in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

• Compounds 7f and 7i exhibited potent antibacterial activity with MIC 1 and 0.5 µg/mL against S. aureus , respectively. • compound 17b exhibited MIC value of 1 µg/mL against M. tuberculosis and drug resistant strains of Mtb. • Nontoxic to Vero cells (CC 50 (>25)) and favorable selectivity index ((S.I.) > 12.5). • Compounds 7f , and 7i , showed potent activity with MIC 0.5-1 µg/mL against MSSA, MRSA, and VRSA isolates. • A topoisomerase inhibition assay and in silico studies were performed to investigate the mechanism of action. The rapid rise in antimicrobial resistance (AMR) has become a major threat to human health. Consequently, the constant search for new antibacterial agents that work against resistant organisms has become a global initiative. To discover new antibacterial agents with improved efficacy and activity against drug-resistant organisms, we designed and synthesized a series of new naphthalimide-coumarin hybrids and evaluated them for their antimicrobial activity against a panel of bacterial and mycobacterial strains. In the preliminary evaluation, compounds 7a, 7c, 7d, 7e, 7f, 7 h, 7i, 7o, 7q, 20a and 20b exhibited potent inhibitory activity against S. aureus ATCC 29213 with MICs in the range of 0.5–32 µg/mL. Compounds 7c, 7d, 7f, 7 h, 7i, 7o, 20a, and 20b also exhibited good inhibitory activity against S. epidermidis with MIC 1–16 µg/mL. All these compounds were found to be non-toxic to Vero cells (CC 50 = >50) and exhibited a favorable selectivity index (SI = >12.5). Additionally, these compounds 7c, 7d, 7e, 7f, 7 h, 7i, 7o, 20a and 20b have shown potent inhibition against various multidrug-resistant strains of S. aureus, including VRSA with MICs in the range of 0.5–16 µg/mL. Interestingly, compound 17b showed potent antimycobacterial activity against M. tuberculosis H37Rv with MIC 1 µg/mL and a favorable selectivity index. It also exhibited potent inhibitory activity against DR-Mtb with MIC 1 µg/mL. Topoisomerase enzyme inhibition assay was carried out to validate the mechanism of action. Furthermore, in silico studies were performed to investigate the binding mode and interactions at the active site of the target enzyme. These results highlight the potential of naphthalimide-coumarin hybrids as novel antimicrobial agents. [Display omitted] [ABSTRACT FROM AUTHOR]

Yanling Liu, Wenhui Li, Qian Dong, Yangqun Liu, Xiaohua Ye School of Public Health, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of ChinaCorrespondence: Yangqun Liu; Xiaohua YeSchool of Public Health, Guangdong Pharmaceutical University, 283# Jianghai Dadao, Haizhu District, Guangzhou, People’s Republic of ChinaTel +862034055355Email 136437677@qq.com; smalltomato@163.comBackground: The distinction between livestock-associated and human-associated methicillin-resistant Staphylococcus aureus (MRSA) has become more and more blurred. This study aimed to reveal the transmission risk of livestock-associated and non-livestock-associated S. aureus (including MRSA and multidrug-resistant S. aureus [MDRSA]) by occupational pig exposure.Methods: A total of 591 pig-exposed workers and 1178 non-exposed workers were enrolled in this study. All nasal S. aureus isolates were tested for antibiotic susceptibility and molecular characteristics. Logistic regression models were used to examine the dose–response relationships between occupational pig exposure and S. aureus carriage.Results: Pig-exposed workers had significantly higher carriage rates of MRSA (OR=6.29, 95% CI: 3.38∼ 11.68) and MDRSA (OR=3.17, 95% CI: 2.03∼ 4.96) than non-exposed workers. Notably, we found dose–response relationships between occupational pig exposure and MRSA or MDRSA carriage. Using genotypic and phenotypic markers for differentiating livestock-associated and non-livestock-associated S. aureus, we also revealed dose–response relationships occupational pig exposure and livestock-associated or non-livestock-associated S. aureus carriage.Conclusion: Our findings provide sufficient epidemiological evidence for revealing the high transmission risk of livestock-associated S. aureus and the low transmission risk of non-livestock-associated S. aureus by occupational pig exposure.Keywords: livestock, human, methicillin-resistant S. aureus, multidrug-resistant S. aureus, transmission

Nelly Hérault, 1,* Julia Wagner, 2–4,* Sarah-Luise Abram, 1 Jérôme Widmer, 2 Lenke Horvath, 1 Dimitri Vanhecke, 5 Carole Bourquin, 2–4,* Katharina M Fromm 1,* 1Department of Chemistry, University of Fribourg, Fribourg 1700, Switzerland; 2Department of Medicine, University of Fribourg, Fribourg 1700, Switzerland; 3Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 1211, Switzerland; 4Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland; 5Adolphe Merkle Institute, University of Fribourg, Fribourg 1700, Switzerland*These authors contributed equally to this workCorrespondence: Katharina M FrommUniversity of Fribourg, PER 10 bu. 114, chemin du Musée 9, Fribourg 1700, SwitzerlandTel +41 26 300 8732Email katharina.fromm@unifr.chBackground: Joint arthroplasty has improved the quality of life of patients worldwide, but infections of the prosthesis are frequent and cause significant morbidity. Antimicrobial coatings for implants promise to prevent these infections.Methods: We have synthesized nanocapsules of titanium dioxide in amorphous or anatase form containing silver as antibacterial agent and tested their impact on bacterial growth. Furthermore, we explored the possible effect of the nanocapsules on the immune system. First, we studied their uptake into macrophages using a combination of electron microscopy and energy-dispersive spectroscopy. Second, we exposed immune cells to the nanocapsules and checked their activation state by flow cytometry and enzyme-linked immunosorbent assay.Results: Silver-containing titanium dioxide nanocapsules show strong antimicrobial activity against both E. coli and S. aureus and even against a multidrug-resistant strain of S. aureus. We could demonstrate the presence of the nanocapsules in macrophages, but, importantly, the nanocapsules did not affect cell viability and did not activate proinflammatory responses at doses up to 20 μg/mL.Conclusion: Our bactericidal silver-containing titanium dioxide nanocapsules fulfill important prerequisites for biomedical use and represent a promising material for the coating of artificial implants.Keywords: silver nanoparticles, titanium dioxide nanocapsules, antimicrobial effect, multidrug-resistant S. aureus, immune cell uptake

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA) are primary causes of skin and soft tissue infections worldwide. To address the emergency caused due to increasing multidrug-resistant (MDR) bacterial infections, a series of novel fluoro and trifluoromethyl-substituted salicylanilide derivatives were synthesized and their antimicrobial activity was investigated. MIC data reveal that the compounds inhibited S. aureus specifically (MIC 0.25–64 µg/mL). The in vitro cytotoxicity of compounds with MIC < 1 µg/mL against Vero cells led to identification of four compounds (20, 22, 24 and 25) with selectivity index above 10. These four compounds were tested against MDR S. aureus panel. Remarkably, 5-chloro-N-(4'-bromo-3'-trifluoromethylphenyl)-2-hydroxybenzamide (22) demonstrated excellent activity against nine MRSA and three VRSA strains with MIC 0.031–0.062 µg/mL, which is significantly better than the control drugs methicillin and vancomycin. The comparative time–kill kinetic experiment revealed that the effect of bacterial killing of 22 is comparable with vancomycin. Compound 22 did not synergize with or antagonize any FDA-approved antibiotic and reduced pre-formed S. aureus biofilm better than vancomycin. Overall, study suggested that 22 could be further developed as a potent anti-staphylococcal therapeutic. [ABSTRACT FROM AUTHOR]

In recent years, the emergence of multidrug-resistant bacteria has limited the selection of drugs for treating bacterial infections, reduced clinical efficacy, and increased treatment costs and mortality. It is urgent to find alternative antibiotics. In order to explore a new method for controlling methicillin-resistant Staphylococcus aureus (S. aureus), this study isolated and purified a multidrug-resistant S. aureus broad-spectrum phage JPL-50 from wastewater. JPL-50 belongs to the Siphoviridae family after morphological observation, biological characterization, and transmission electron microscopy (TEM) fragmentation spectrum analysis. It can cleave 84% of tested S. aureus (168/200), in which 100% of tested mastitis-associated strains (48/48) and 72.04% of MRSA strains (67/93) were lysed. In addition, it has an optimal growth temperature of about 30°C, a high activity within a wide pH range (pH 3-10), and an optimal multiplicity of infection of 0.01. The one-step growth curve shows a latent time of 20 min, an explosive time of 80 min. JPL-50 was 16 927 bp in length and was encoded by double-stranded DNA, with no genes associated with bacterial resistance or virulence factors detected. In a therapeutic study, injection of the phage JPL-50 once and for 7 times in 7 days protected 40% and 60% of the mice from fatal S. aureus infection, respectively. More importantly, JPL-50-doxycycline combination could effectively inhibit host S. aureus in vitro and reduce the use of doxycycline within 8 h. In conclusion, the bacteriophage JPL-50 has a wide lysis spectrum, high lysis rate, high tolerance to extreme environments, and moderate in vivo activity, providing ideas for developing multidrug-resistant S. aureus infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

While some studies have defined Staphylococcus aureus based on its clonal complex and resistance pattern, few have explored the relations between the genetic lineages and antibiotic resistance patterns and immune evasion cluster (IEC) genes. Our aim was to investigate the potential relationship between phenotypic and molecular characteristics so as to reveal livestock-associated S. aureus in humans. The study participants were interviewed, and they provided two nasal swabs for S. aureus analysis. All S. aureus and methicillin-resistant S. aureus (MRSA) were tested for antibiotic susceptibility, multilocus sequence type and IEC genes. Of the 1162 participants, 9.3% carried S. aureus, including MRSA (1.4%) and multidrug-resistant S. aureus (MDRSA, 2.8%). The predominant multidrug-resistant pattern among MDRSA isolates was nonsusceptibility to erythromycin, clindamycin and tetracycline. The most common S. aureus genotypes were ST7, ST6, ST188 and ST59, and the predominant MRSA genotype was ST7. Notably, the livestock-associated S. aureus isolates (IEC-negative CC9, IEC-negative tetracycline-resistant CC398, and IEC-negative tetracycline-resistant CC5) were found in people with no occupational livestock contact. These findings reveal a potential relationship between S. aureus CCs and IEC genes and antibiotic resistance patterns in defining livestock-associated S. aureus in humans and support growing concern about the potential livestock-to-human transmission of livestock-associated S. aureus by non-occupational livestock contact.

To address the emergency caused by multi-drug resistant Staphylococcus aureus , a series of novel capsaicin derivatives with nitrothiophene substituents have been designed and evaluated for the antibacterial activities against S. aureus Newman and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). The structure-activity relationship was further revealed. Compound 13c , 13f , and 13g were highly active against staphylococcal growth, with minimal inhibition concentration (MIC) values of 0.39–1.56 μg/mL. The oxadiazole-derived compound 21 , a bioisostere of ester 13f , is the most potent candidate for anti-growth of five multidrug-resistant S. aureus strains with MICs of 0.20–0.78 μg/mL, which is more active compared with vancomycin in vitro. Notably, these anti-staphylococcal compounds are much less cytotoxic to the normal kidney epithelial cell line (HK293T). Image 1 • Capsaicin derivatives with nitrothiophene substituents have been designed and synthesized. • Compoud 13c was most potent against S. aureus Newman strain. • Compoud 21 showed excellent antibacterial activity against MDR S. aureus strains. • The potent compounds showed no obvious toxicity to normal cell line HK293T. [ABSTRACT FROM AUTHOR]

S. aureus is resistant to various first-line antibiotics, and seeking multifarious strategies aimed at effective control of antibiotic-resistant behavior is urgently needed. Here, we report a two-component directed self-assembly mode: the phytochemicals berberine and cinnamic acid can directly self-assemble into nanoparticles (NPs) displaying good bacteriostastic activity. Compared with several first-line antibiotics, the obtained nanostructures have a better inhibitory effect on multidrug-resistant S. aureus (MRSA) and stronger ability for biofilm removal. These qualities are attributed to the fact that organic assemblies can first spontaneously adhere to the surface of the bacteria, infiltrate into the cell, and then lead to converging attack against MRSA; thereafter, multipath bactericidal mechanisms of NPs on MRSA are found by both transcriptomic analysis and quantitative Polymerase Chain Reaction analysis. Moreover, when combined with spectral data and single crystal X-ray diffraction, the NPs' self-assembly mechanism governed by hydrogen bonds and π-π stacking interactions is clearly elucidated. These non-covalent interactions induce the NPs' formation of butterfly-like one-dimensional self-assembled units and finally layered three-dimensional spatial configuration. In addition, biocompatibility tests show that the NPs are nonhemolytic with little toxicity in vitro and in vivo. This directed self-assembly mode can offer a new perspective toward the design of biocompatible antimicrobial nanomedicines for clinical translation.

While some studies have defined Staphylococcus aureus based on its clonal complex and resistance pattern, few have explored the relations between the genetic lineages and antibiotic resistance patterns and immune evasion cluster (IEC) genes. Our aim was to investigate the potential relationship between phenotypic and molecular characteristics so as to reveal livestock-associated S. aureus in humans. The study participants were interviewed, and they provided two nasal swabs for S. aureus analysis. All S. aureus and methicillin-resistant S. aureus (MRSA) were tested for antibiotic susceptibility, multilocus sequence type and IEC genes. Of the 1162 participants, 9.3% carried S. aureus , including MRSA (1.4%) and multidrug-resistant S. aureus (MDRSA, 2.8%). The predominant multidrug-resistant pattern among MDRSA isolates was non-susceptibility to erythromycin, clindamycin and tetracycline. The most common S. aureus genotypes were ST7, ST6, ST188, and ST59, and the predominant MRSA genotype was ST7. Notably, the livestock-associated S. aureus isolates (IEC-negative CC9, IEC-negative tetracycline-resistant CC398, and IEC-negative tetracycline-resistant CC5) were found in people with no occupational livestock contact. These findings reveal a potential relationship between S. aureus CCs and IEC genes and antibiotic resistance patterns in defining livestock-associated S. aureus in humans and support growing concern about the potential livestock-to-human transmission of livestock-associated S. aureus by non-occupational livestock contact.