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Mechanisms of Resistance

Novel Mechanisms of Efflux-Mediated Levofloxacin Resistance and Reduced Amikacin Susceptibility in Stenotrophomonas maltophilia

Punyawee Dulyayangkul, Karina Calvopiña, Kate J. Heesom, Matthew B. Avison
Punyawee Dulyayangkul
aSchool of Cellular & Molecular Medicine, University of Bristol, Bristol, United Kingdom
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Karina Calvopiña
aSchool of Cellular & Molecular Medicine, University of Bristol, Bristol, United Kingdom
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Kate J. Heesom
bUniversity of Bristol Proteomics Facility, Bristol, United Kingdom
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Matthew B. Avison
aSchool of Cellular & Molecular Medicine, University of Bristol, Bristol, United Kingdom
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  • ORCID record for Matthew B. Avison
DOI: 10.1128/AAC.01284-20
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ABSTRACT

Fluoroquinolone resistance in Stenotrophomonas maltophilia is multifactorial, 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 SmaRS). The sensor kinase Smlt2646 (SmaS) is activated by mutation in K M6 LEVr causing overproduction of two novel ABC transporters and the known aminoglycoside efflux pump SmeYZ. Overproduction of one ABC transporter, Smlt1651-4 (renamed SmaCDEF), causes levofloxacin resistance in K M6 LEVr. Overproduction 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.

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Novel Mechanisms of Efflux-Mediated Levofloxacin Resistance and Reduced Amikacin Susceptibility in Stenotrophomonas maltophilia
Punyawee Dulyayangkul, Karina Calvopiña, Kate J. Heesom, Matthew B. Avison
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01284-20; DOI: 10.1128/AAC.01284-20

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Novel Mechanisms of Efflux-Mediated Levofloxacin Resistance and Reduced Amikacin Susceptibility in Stenotrophomonas maltophilia
Punyawee Dulyayangkul, Karina Calvopiña, Kate J. Heesom, Matthew B. Avison
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01284-20; DOI: 10.1128/AAC.01284-20
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KEYWORDS

ABC transporters
efflux pumps
proteomics
two-component regulatory systems

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