Resistance to pentamidine is mediated by AdeAB, regulated by AdeRS, and influenced by growth conditions in Acinetobacter baumannii ATCC 17978

Abstract

In recent years, effective treatment of infections caused by Acinetobacter baumannii has become challenging due to the ability of the bacterium to acquire or up-regulate antimicrobial resistance determinants. Two component signal transduction systems are known to regulate expression of virulence factors including multidrug efflux pumps. Here, we investigated the role of the AdeRS two component signal transduction system in regulating the AdeAB efflux system, determined whether AdeA and/or AdeB can individually confer antimicrobial resistance, and explored the interplay between pentamidine resistance and growth conditions in A. baumannii ATCC 17978. Results identified that deletion of adeRS affected resistance towards chlorhexidine and 4’,6-diamidino-2-phenylindole dihydrochloride, two previously defined AdeABC substrates, and also identified an 8-fold decrease in resistance to pentamidine. Examination of ΔadeA, ΔadeB and ΔadeAB cells augmented results seen for ΔadeRS and identified a set of dicationic AdeAB substrates. RNA-sequencing of ΔadeRS revealed transcription of 290 genes were ≥2-fold altered compared to the wildtype. Pentamidine shock significantly increased adeA expression in the wildtype, but decreased it in ΔadeRS, implying that AdeRS activates adeAB transcription in ATCC 17978. Investigation under multiple growth conditions, including the use of Biolog phenotypic microarrays, revealed resistance to pentamidine in ATCC 17978 and mutants could be altered by bioavailability of iron or utilization of different carbon sources. In conclusion, the results of this study provide evidence that AdeAB in ATCC 17978 can confer intrinsic resistance to a subset of dicationic compounds and in particular, resistance to pentamidine can be significantly altered depending on the growth conditions.

<p>Comparative genomic analysis and multi-drug resistance differences of <em>Acinetobacter baumannii</em> in Chongqing, China</p>

“…Members of the Ade ABC efflux pump family are currently the main determinants of antibiotic resistance. Due to their active efflux activities, their expression has extensive effects on antibiotic resistance, including against aminoglycosides, trimethoprim, and quinolones 37. In MDR-CQJ, the AdeS gene harbored a C to T mutation at position 281 in the coding region, corresponding to amino acid change A94V, which resulted in increased expression and downstream regulation.…”

A Whole-Cell Screen Identifies Small Bioactives That Synergize with Polymyxin and Exhibit Antimicrobial Activities against Multidrug-Resistant Bacteria

“…In the interim, other groups have pursued developing polymyxin-sparing regimes, such as pentamidine, in order to avoid the clinical use of polymyxins and circumvent their inherent toxicity (29). However, new evidence has already emerged that A. baumannii can develop intrinsic resistance to pentamidine (89), which just further illustrates the importance of continued investigation into polymyxin resistance mechanisms and the constant need for new therapeutic interventions.…”

Roles of two-component regulatory systems in antibiotic resistance

“…baumannii has at least two TCSs that upregulate MDR efflux pumps. The first, AdeRS, activates the AdeABC MDR pump, and the second, BaeSR, also activates AdeABC as well as two other pumps: AdeIJK and MacAB-TolC [38][39][40][41][42][43][44]49]. In E. coli, BaeSR acts similarly, activating the mdtABCD gene cluster encoding a multidrug transporter [50,51].…”