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Oxadiazolone derivatives block Staphylococcus aureus growth and biofilm formation by covalently binding to strategic (Ser/Cys)-based enzymes

ABSTRACT: Staphylococcus aureus is a Gram-positive opportunistic pathogen and a top-priority bacterium in the fight against antimicrobial resistance. Its high propensity to mutate, develop resistance, and become more virulent, as well as its ability to form biofilms, results in difficult-to-treat infections against which new chemical classes are urgently needed. Here, we investigated the antibacterial activity of oxadiazolone-core derivatives (OX) against planktonic and biofilm-associated S. aureus. Among the tested compounds, MpPPOX exhibits a strong bactericidal effect on extracellular bacteria with similar MIC to that of Vancomycin; iBPOX mainly inhibits intracellular bacterial growth; while HPOX strongly impair biofilm formation. Such a divergence in activity prompted us to identify their potential target enzymes via activity-based protein profiling combined with mass spectrometry. Although the most active MpPPOX inhibitor targets multiple (Ser/Cys)-based enzymes, the antibiofilm HPOX compound primarily reacts with enzymes involved in biofilm formation and virulence. Among them, the FabH protein has been confirmed as a vulnerable target of MpPPOX. Overall, this study underscores the multi-target nature of the OXs covalently bind to several (Ser/Cys)-based enzymes of interest. This binding property makes them highly versatile chemotypes that could be used as broad-spectrum antimicrobial and anti-virulence agents to potentiate otherwise ineffective or poorly active drugs.

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ORGANISM(S): Staphylococcus Aureus

SUBMITTER: AUDEBERT Stephane

LAB HEAD: Stéphane Audebert, PhD

PROVIDER: PXD073012 | Pride | 2026-04-01

REPOSITORIES: Pride

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Project description:Long term-catheterization leads inevitably to a catheter-associated bacteriuria caused by multispecies bacterial biofilms growing on and in the catheters. The overall goal of the presented study was (I) to unravel bacterial community structure and function of such an uropathogenic biofilm and (II) to elucidate the interplay between bacterial virulence and the human immune system within the urine. To this end, a metaproteomics approach combined with in vitro proteomics analyses was employed to investigate both, the pro- and eukaryotic protein inventory. Our proteome analyses demonstrated that the biofilm of the investigated catheter is dominated by three bacterial species, i.e. Pseudomonas aeruginosa, Morganella morganii and Bacteroides sp., and identified iron limitation as one of the major challenges in the bladder environment. In vitro proteome analysis of P. aeruginosa and M. morganii isolated from the biofilm revealed that those opportunistic pathogens are able to overcome iron restriction via the production of siderophores and high expression of corresponding receptors. Notably, a comparison of in vivo and in vitro protein profiles of P. aeruginosa and M. morganii also indicated that the bacteria employ different strategies to adapt to the urinary tract. Whilst P. aeruginosa seems to express secreted and surface-exposed proteases to escape the human innate immune system and metabolizes amino acids, M. morganii is able to take up sugars and to degrade urea. Most interestingly, a comparison of urine protein profiles of three long-term catheterized patients and three healthy control persons demonstrated the elevated level of proteins associated to neutrophils, macrophages and complement system in the patient urine, which might point to a specific activation of the innate immune system in response to biofilm-associated urinary tract infections. We thus hypothesize that the often asymptomatic nature of CAUTI´s might be based on a fine-tuned balance between the expression of bacterial virulence factors and the human immune system. Long term-catheterization leads inevitably to a catheter-associated bacteriuria caused by multispecies bacterial biofilms growing on and in the catheters. The overall goal of the presented study was (I) to unravel bacterial community structure and function of such an uropathogenic biofilm and (II) to elucidate the interplay between bacterial virulence and the human immune system within the urine. To this end, a metaproteomics approach combined with in vitro proteomics analyses was employed to investigate both, the pro- and eukaryotic protein inventory. Our proteome analyses demonstrated that the biofilm of the investigated catheter is dominated by three bacterial species, i.e. Pseudomonas aeruginosa, Morganella morganii and Bacteroides sp., and identified iron limitation as one of the major challenges in the bladder environment. In vitro proteome analysis of P. aeruginosa and M. morganii isolated from the biofilm revealed that those opportunistic pathogens are able to overcome iron restriction via the production of siderophores and high expression of corresponding receptors. Notably, a comparison of in vivo and in vitro protein profiles of P. aeruginosa and M. morganii also indicated that the bacteria employ different strategies to adapt to the urinary tract. Whilst P. aeruginosa seems to express secreted and surface-exposed proteases to escape the human innate immune system and metabolizes amino acids, M. morganii is able to take up sugars and to degrade urea. Most interestingly, a comparison of urine protein profiles of three long-term catheterized patients and three healthy control persons demonstrated the elevated level of proteins associated to neutrophils, macrophages and complement system in the patient urine, which might point to a specific activation of the innate immune system in response to biofilm-associated urinary tract infections. We thus hypothesize that the often asymptomatic nature of CAUTI´s might be based on a fine-tuned balance between the expression of bacterial virulence factors and the human immune system.

			Action	DRS
	HPOXyne11.raw	Raw
	HPOXyne11_20240217190742.raw	Raw
	HPOXyne12.raw	Raw
	HPOXyne12_20240217235542.raw	Raw
	HPOXyne21.raw	Raw

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Oxadiazolone derivatives block Staphylococcus aureus growth and biofilm formation by covalently binding to strategic (Ser/Cys)-based enzymes

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