Work

Macromolecular alterations in Staphylococcus spp.: Pyrrolomycin-induced changes in the anomeric configuration of wall teichoic acids, membrane fluidity, staphyloxanthin induction, and protein structure and functionality

Year: 2025

Type: article

Abstract: Antimicrobial resistance (AMR) is one of the most alarming global challenges of modern society. Among the pathogens of great concern are staphylococci, Gram-positive bacteria typically inhabiting the nasal microbiome that have developed multidrug-resistant (MDR) traits, complicating treatment strategies. This study examines the antimicrobial efficacy of pyrrolomycins (PMs), unique polyhalogenated antibiotics, against sensitive and MDR Staphylococcus strains. By employing a multidisciplinary approach, we combine physical-chemical methodologies alongside analytical and biological techniques to shed light on the PM mode of action. The findings elucidate the complex mechanisms by which PMs exert their antimicrobial effects, including disruption of cell wall polysaccharides, modulation of the fatty acid profile, induction of membrane depolarization, enhancement of carotenoid staphyloxanthin production, impairment of bacterial oxidative damage responses, and protein structural and functional alterations. Collectively, PMs' striking effects inexorably alter the physiological bacterial fitness, culminating in bacterial cell death. Although staphylococci may develop limited adaptive mechanisms to PMs, these adaptations appear insufficient to confer resistance, reducing the potential for AMR against these biocidal compounds. This comprehensive analysis underscores the promise of PMs as a novel therapeutic avenue against MDR staphylococcal infections, providing crucial insights for advancing drug development in the ongoing battle against AMR. The natural polyhalogenated antibiotic pyrrolomycins are promising candidates to counteract the global threat represented by antimicrobial-resistant pathogens, as these compounds efficiently inhibit the growth of multidrug-resistant Staphylococcus species. Utilizing a multidisciplinary biophysical-chemical approach integrating spectroscopic and imaging approaches with biological assays, this study elucidates the pyrrolomycin mode of action and potential resistance mechanisms in Staphylococcus species. Key findings reveal that pyrrolomycins disrupt the cell wall, alter the cell membrane in terms of composition, fluidity, and polarization, stimulate staphyloxanthin production, impair oxidative damage responses, and modify protein structures and functions, compromising cell viability and physiological fitness. • Pyrrolomycins (PMs) show promise in combating multidrug-resistant staphylococci • Nitro-PM modifies the bacterial cell-wall polysaccharides impairing its structure • PMs act as a bridge for lipid head groups causing membrane alterations • Nitro-PM causes bacterial electrophilic stress via reactive oxygen species generation • Nitro-PM enhances nucleophilic aromatic substitution reactions altering protein structure • PMs induce staphyloxanthin and thiol production as a tentative bacterial response

Source: International Journal of Biological Macromolecules

DOI: 10.1016/j.ijbiomac.2025.147924