Transcriptomics Reveals How Minocycline-Colistin Synergy Overcomes Antibiotic Resistance in Multidrug-Resistant Klebsiella pneumoniae.

Antimicrob Agents Chemother
Authors
Keywords
Abstract

Multidrug-resistant Gram-negative bacteria are a rapidly growing public health threat, and the development of novel antimicrobials has failed to keep pace with their emergence. Synergistic combinations of individually ineffective drugs present a potential solution, yet little is understood about the mechanisms of most such combinations. Here, we show that the combination of colistin (polymyxin E) and minocycline has a high rate of synergy against colistin-resistant and minocycline-intermediate or -resistant strains of Klebsiella pneumoniae. Furthermore, using transcriptome sequencing (RNA-Seq), we characterized the transcriptional profiles of these strains when treated with the drugs individually and in combination. We found a striking similarity between the transcriptional profiles of bacteria treated with the combination of colistin and minocycline at individually subinhibitory concentrations and those of the same isolates treated with minocycline alone. We observed a similar pattern with the combination of polymyxin B nonapeptide (a polymyxin B analogue that lacks intrinsic antimicrobial activity) and minocycline. We also found that genes involved in polymyxin resistance and peptidoglycan biosynthesis showed significant differential gene expression in the different treatment conditions, suggesting possible mechanisms for the antibacterial activity observed in the combination. These findings suggest that the synergistic activity of this combination against bacteria resistant to each drug alone involves sublethal outer membrane disruption by colistin, which permits increased intracellular accumulation of minocycline.

Year of Publication
2022
Journal
Antimicrob Agents Chemother
Volume
66
Issue
3
Pages
e0196921
Date Published
2022 03 15
ISSN
1098-6596
DOI
10.1128/aac.01969-21
PubMed ID
35041511
PubMed Central ID
PMC8923212
Links
Grant list
T32 AI007061 / AI / NIAID NIH HHS / United States
T32 HD055148 / HD / NICHD NIH HHS / United States
K08 AI132716 / AI / NIAID NIH HHS / United States
U19 AI110818 / AI / NIAID NIH HHS / United States