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.

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.