Adamiak Justyna W, Bergen Charles, Ajmal Laiba, Reddy Sidhvi, Anderson Paolla Gruber, Rybenkov Valentin V, Zgurskaya Helen I
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.
Appl Environ Microbiol. 2025 Sep 17;91(9):e0122325. doi: 10.1128/aem.01223-25. Epub 2025 Aug 18.
is an opportunistic human pathogen that is ubiquitous in the environment. The environmental versatility of is often attributed to a large arsenal of active efflux pumps, low permeability of the outer membrane, and extensive regulatory networks. In this study, we analyzed putative functional interplay between polyspecific drug efflux pumps of the Resistance-Nodulation-Division (RND) superfamily of proteins and the GacSA two-component regulatory system. RND transporters are the major contributors to antibiotic resistance and survival under various environmental stresses, whereas GacSA is a global regulator and governs critical lifestyles during human colonization. We found that the inactivation of either RND pumps or induces broad, partially overlapping responses in lifestyle (e.g., rhamnolipid biosynthesis, heat shock response, and quorum sensing), virulence (e.g., proteases, toxins, and phenazines secretion systems), and metabolic programs (e.g., electron, iron capture, synthesis/degradation of ketone bodies, and cyanoamino acid metabolism) that are more pronounced during the exponential than the stationary phase. GacSA and RND efflux pumps induced opposite responses in the gene expression of , whereas the overexpression of GacS was additive with the deletion of efflux pumps in gene expression and under growth conditions typically associated with human infections such as elevated temperature and iron deprivation. We conclude that RND efflux and GacSA networks partially overlap with each other.IMPORTANCERND efflux pumps are the major contributors to intrinsic and clinical levels of antibiotic resistance of and their expression is regulated by various environmental factors. However, functional relationships between active efflux pumps and regulatory networks involved in virulence and pathogenesis of remain unclear. This study showed that the loss of RND-dependent efflux functions or the inactivation of the pathway induces partially overlapping transcriptional and physiological responses, suggesting that these pathways could be complementary to each other in hostile environments.
是一种机会性人类病原体，在环境中普遍存在。其环境适应性通常归因于大量活跃的外排泵、外膜的低渗透性以及广泛的调控网络。在本研究中，我们分析了抗药-固氮-细胞分裂（RND）超家族蛋白质的多特异性药物外排泵与GacSA双组分调控系统之间假定的功能相互作用。RND转运蛋白是抗生素耐药性以及在各种环境压力下生存的主要贡献者，而GacSA是一种全局调控因子，在人类定植期间控制关键的生活方式。我们发现，RND泵或 的失活会在生活方式（如鼠李糖脂生物合成、热休克反应和群体感应）、毒力（如蛋白酶、毒素和吩嗪分泌系统）以及代谢程序（如电子、铁捕获、酮体的合成/降解和氰基氨基酸代谢）中引发广泛的、部分重叠的反应，这些反应在指数生长期比稳定期更为明显。GacSA和RND外排泵在 的基因表达中引发相反的反应，而在基因表达以及在通常与人类感染相关的生长条件（如高温和缺铁）下，GacS的过表达与外排泵的缺失具有累加效应。我们得出结论，RND外排和GacSA网络彼此部分重叠。重要性RND外排泵是 抗生素耐药性内在和临床水平的主要贡献者，其表达受多种环境因素调控。然而，活跃外排泵与参与 毒力和发病机制的调控网络之间的功能关系仍不清楚。本研究表明，RND依赖的外排功能丧失或 途径的失活会引发部分重叠的转录和生理反应，表明这些途径在恶劣环境中可能相互补充。
