Novel mechanisms of efflux-mediated levofloxacin resistance and reduced amikacin susceptibility in Stenotrophomonas maltophilia

Punyawee Dulyayangkul, Karina A Calvopina, Kate J Heesom, Matthew B Avison*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Fluoroquinolone resistance in Stenotrophomonas maltophilia is multi-factorial, but the most significant factor is overproduction of efflux pumps, particularly SmeDEF, following mutation. Here we report that mutations in the glycosyl transferase gene smlt0622 in S. maltophilia K279a mutant K M6 cause constitutive activation of SmeDEF production, leading to elevated levofloxacin MIC. Selection of a levofloxacin-resistant K M6 derivative, K M6 LEVR, allowed identification of a novel two-component regulatory system, Smlt2645/6 (renamed as SmaRS). The sensor kinase Smlt2646 (SmaS) is activated by mutation in K M6 LEVR causing over-production of two novel ABC transporters and the known aminoglycoside efflux pump SmeYZ. Over-production of one ABC transporter, Smlt1651-4 (renamed as SmaCDEF) causes levofloxacin resistance in K M6 LEVR. Over-production of the other ABC transporter, Smlt2642/3 (renamed SmaAB) and SmeYZ both contribute to the elevated amikacin MIC against K M6 LEVR. Accordingly, we have identified two novel ABC transporters associated with antimicrobial drug resistance in S. maltophilia, and two novel regulatory systems whose mutation causes resistance to levofloxacin, clinically important as a promising drug for monotherapy against this highly resistant pathogen.
Original languageEnglish
JournalAntimicrobial Agents and Chemotherapy
Publication statusAccepted/In press - 27 Oct 2020

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