Genomic alterations involved in fluoroquinolone resistance development in Staphylococcus aureus

Thuc Quyen Huynh, Van Nhi Tran, Van Thai, Hoang An Nguyen, Ngoc Thuy Giang Nguyen, Minh Khang Tran, Thi Phuong Truc Nguyen, Cat Anh Le, Le Thanh Ngan Ho, Navenaah Udaya Surian, Swaine Chen, Thi Thu Hoai Nguyen

Research output: Contribution to journalArticlepeer-review

Abstract

Aim
Fluoroquinolone (FQ) is a potent antibiotic class. However, resistance to this class emerges quickly which hinders its application. In this study, mechanisms leading to the emergence of multidrug-resistant (MDR) Staphylococcus aureus (S. aureus) strains under FQ exposure were investigated.

Methodology
S. aureus ATCC 29213 was serially exposed to ciprofloxacin (CIP), ofloxacin (OFL), or levofloxacin (LEV) at sub-minimum inhibitory concentrations (sub-MICs) for 12 days to obtain S. aureus -1 strains and antibiotic-free cultured for another 10 days to obtain S. aureus-2 strains. The whole genome (WGS) and target sequencing were applied to analyze genomic alterations; and RT-qPCR was used to access the expressions of efflux-related genes, alternative sigma factors, and genes involved in FQ resistance.

Results
A strong and irreversible increase of MICs was observed in all applied FQs (32 to 128 times) in all S. aureus-1 and remained 16 to 32 times in all S. aureus-2. WGS indicated 10 noticeable mutations occurring in all FQ-exposed S. aureus including 2 insdel mutations in SACOL0573 and rimI; a synonymous mutation in hslO; and 7 missense mutations located in an untranslated region. GrlA, was found mutated (R570H) in all S. aureus-1 and -2. Genes encoding for efflux pumps and their regulator (norA, norB, norC, and mgrA); alternative sigma factors (sigB and sigS); acetyltransferase (rimI); methicillin resistance (fmtB); and hypothetical protein BJI72_0645 were overexpressed in FQ-exposed strains.

Conclusion
The emergence of MDR S. aureus was associated with the mutations in the FQ-target sequences and the overexpression of efflux pump systems and their regulators
Original languageEnglish
Article numbere0287973
Number of pages21
JournalPLoS One
Volume18
Issue number7 July
DOIs
Publication statusPublished - 26 Jul 2023
Externally publishedYes

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