Adjunctive therapy for multidrug-resistant bacterial infections: Type III secretion system and efflux inhibitors. Issue 9 (September 2021)

• Record Type: Journal Article
• Authors: Moir, Donald T.; Opperman, Timothy J.; Aron, Zachary D.; Bowlin, Terry L.
• Is Part Of: Drug discovery today. Volume 26:Issue 9(2021)
• Page Start: 2173
• Page End: 2181
• Publication Date: 2021-09
• Subjects: Adjunctive therapy -- Anti-virulence -- P. aeruginosa -- Type III secretion -- Efflux pump inhibitor -- Enterobacteriaceae; Drugs -- Design -- Periodicals; Drugs -- Research -- Periodicals; 615.1
• DOI: 10.1016/j.drudis.2021.03.031
• Languages: English
• ISSNs: 1359-6446

Abstract

Highlights: Gram-negative pathogens rely on intrinsic resistance and virulence factors during infection. Many of these factors are attractive, but underutilized, targets for antibacterial drugs. Novel anti-resistance and anti-virulence drugs may be useful adjuncts to approved antibiotics to improve treatment outcomes. This review summarizes optimization of novel inhibitors of the T3SS of P. aeruginosa, an important virulence factor. This review describes inhibitors of a major intrinsic resistance mechanism, the RND-type efflux pumps. Abstract: The increasing prevalence of multidrug-resistant (MDR) bacterial infections has created a crucial need for new therapeutics that avoid or minimize existing resistance mechanisms. In this review, we describe the development of novel classes of small-molecule adjunctive agents targeting either a bacterial virulence factor, the Pseudomonas aeruginosa type III secretion system (T3SS), or an intrinsic resistance factor, resistance-nodulation-cell division superfamily (RND) efflux pumps of the Enterobacteriaceae . These agents are designed to be administered with antibacterials to improve their efficacy. T3SS inhibition rescues host innate immune system cells from injection with bacterial toxins, whereas RND efflux pump inhibition increases antibiotic susceptibility, in both cases improving the efficacy of the combined antibacterial.