A Virulence Associated Siderophore Importer Reduces Antimicrobial Susceptibility of Klebsiella pneumoniae.

Kumar Rajakumar,Helen M O’Hare,Marco R Oggioni,Primrose P E Freestone,Michael R Barer,Robeena Farzand,Galina V Mukamolova

doi:10.3389/fmicb.2021.607512

Kumar Rajakumar, Helen M O’Hare + Show 5 more

Open Access

https://doi.org/10.3389/fmicb.2021.607512

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Abstract

The accessory genomes of many pathogenic bacteria include ABC transporters that scavenge metal by siderophore uptake and ABC transporters that contribute to antimicrobial resistance by multidrug efflux. There are mechanistic and recently recognized structural similarities between siderophore importer proteins and efflux pumps. Here we investigated the influence of siderophore importer YbtPQ on antimicrobial resistance of Klebsiella pneumoniae. YbtPQ is encoded in the yersiniabactin cluster in a prevalent mobile genetic element ICEKp, and is also common in pathogenicity islands of Escherichia coli and Yersinia species, where yersiniabactin enhances virulence. Deletion of ICEKp increased the susceptibility of K. pneumoniae to all antimicrobials tested. The mechanism was dependent on the yersiniabactin importer YbtPQ and may involve antimicrobial efflux, since it was affected by the inhibitor reserpine. The element ICEKp is naturally highly mobile, indeed the accessory genome of K. pneumoniae is recognized as a reservoir of genes for the emergence of hospital outbreak strains and for transfer to other Gram-negative pathogens. Introduction of ICEKp, or a plasmid encoding YbtPQ, to E. coli decreased its susceptibility to a broad range of antimicrobials. Thus a confirmed siderophore importer, on a rapidly evolving and highly mobile element capable of interspecies transfer, may have a secondary function exporting antimicrobials.

Highlights

ABC transporters in the accessory genomes of bacterial pathogens significantly influence both virulence and antimicrobial resistance
We found that YbtPQ was necessary and sufficient to confer a modest but significant reduction in susceptibility for a broad range of antimicrobials on both organisms, even in the absence of the rest of the yersiniabactin cluster or external yersiniabactin
We demonstrate that the yersiniabactin cluster of K. pneumoniae affects antimicrobial susceptibility via the transporter YbtPQ, and this trait can be transmitted by conjugation to E. coli and potentially other pathogenic Enterobacteriaceae

Summary

Introduction

ABC transporters in the accessory genomes of bacterial pathogens significantly influence both virulence and antimicrobial resistance. Siderophore importers scavenge metals from the host and efflux pumps export antimicrobials, and the presence of such transporters on mobile genetic elements is associated with both disease severity and treatment failure. The nature of this transport is specific and unidirectional, due to the specific interactions between substrate and binding cavity, and the asymmetry of ATP-powered. Broad-specificity multidrug efflux pumps are an apparent exception, and these have binding cavities with multiple sites that can interact with diverse antimicrobials (Du et al, 2018). Bidirectional ABC transporters that import one substrate and export another, are compatible with the mechanistic models but are unknown

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