A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeaeShow others and affiliations
2022 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 66, no 5, article id e0025122Article in journal (Refereed) Published
Abstract [en]
The continued emergence of Neisseria gonorrhoeae isolates which are resistant to first-line antibiotics has reinvigorated interest in alternative therapies such as expanded use of gentamicin (Gen). We hypothesized that expanded use of Gen promotes emergence of gonococci with clinical resistance to this aminoglycoside. To understand how decreased susceptibility of gonococci to Gen might develop, we selected spontaneous low-level Gen-resistant (GenR) mutants (Gen MIC = 32 μg/mL) of the Gen-susceptible strain FA19. Consequently, we identified a novel missense mutation in fusA, which encodes elongation factor G (EF-G), causing an alanine (A) to valine (V) substitution at amino acid position 563 in domain IV of EF-G; the mutant allele was termed fusA2. Transformation analysis showed that fusA2 could increase the Gen MIC by 4-fold. While possession of fusA2 did not impair either in vitro gonococcal growth or protein synthesis, it did result in a fitness defect during experimental infection of the lower genital tract in female mice. Through bioinformatic analysis of whole-genome sequences of 10,634 international gonococcal clinical isolates, other fusA alleles were frequently detected, but genetic studies revealed that they could not decrease Gen susceptibility in a similar manner to fusA2. In contrast to these diverse international fusA alleles, the fusA2-encoded A563V substitution was detected in only a single gonococcal clinical isolate. We hypothesize that the rare occurrence of fusA2 in N. gonorrhoeae clinical isolates is likely due to a fitness cost during infection, but compensatory mutations which alleviate this fitness cost could emerge and promote GenR in global strains.
Place, publisher, year, edition, pages
American Society for Microbiology , 2022. Vol. 66, no 5, article id e0025122
Keywords [en]
Neisseria gonorrhoeae, fusA, gentamicin, resistance, spontaneous mutant
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:oru:diva-98802DOI: 10.1128/aac.00251-22ISI: 000788108400001PubMedID: 35465683Scopus ID: 10.1128/aac.00251-22OAI: oai:DiVA.org:oru-98802DiVA, id: diva2:1655917
Note
Funding agencis:
United States Department of Health & Human Services
National Institutes of Health (NIH) - USA R01 AI 147609
US Department of Veterans Affairs
2022-05-042022-05-042022-06-17Bibliographically approved