PubMed · 2755487
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J Mowles, S Moran, A Doyle. 1989-08-03. Mycoplasma control.. https://doi.org/10.1038/340352c0
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Methicillin-resistant Staphylococcus aureus (MRSA) is a globally significant pathogen causing severe infections. The chronicity and recurrence of its infection pose serious challenges to public health. In this study, we reported that intracellular accumulation of α-ketoglutarate (α-KG) significantly increased ciprofloxacin (CIP) tolerance in MRSA. Using integrated metabolomic and functional genomic approaches, we demonstrated that both exogenous α-KG and genetic knockout of α-KG dehydrogenase (ΔsucA, ΔsucB) induced CIP tolerance in MRSA. Mechanistically, elevated α-KG levels drive the accumulation of glutamate (Glu), which in turn reduced bacterial membrane potential and cellular ATP content. Furthermore, Glu accumulation raised intracellular osmotic pressure, leading to decreased CIP uptake. These metabolic alterations enable MRSA to sustain high tolerance toward ciprofloxacin. Our findings reveal a key role of the α-KG-Glu metabolic axis in driving antibiotic tolerance and provide novel insights into the metabolic adaptations underlying drug persistence in MRSA.
In a multicentre study, the methicillin-resistant Staphylococcus aureus (MRSA) isolates in 19 large clinics in Germany were recorded, and the resistance characteristics of these strains were studied. Oxacillin-mannitol-salt agar plates were distributed to all participants to ensure uniformity of screening, and each laboratory used these plates to investigate 200 consecutive Staphylococcus aureus isolates for oxacillin-methicillin resistance. Of the 3,794 evaluable Staphylococcus aureus isolates, 71.5% were penicillin and 3.7% (142) oxacillin resistant; four study centres reported methicillin-oxacillin resistance rates of more than 5%. Of the MRSA isolates, 75% were also resistant to ciprofloxacin, 61% to fosfomycin, 52% to imipenem, 50% to trimethoprim/sulfamethoxazole and 36% to clindamycin. All isolates were sensitive to vancomycin and teicoplanin. Of the Staphylococcus aureus strains isolated from patients in intensive therapy units, 10.4% were methicillin-oxacillin resistant. Drains and catheter tips (9.8% and 5.2% respectively) were the materials with the highest proportions of MRSA. Of the MRSA isolates in this study, 58.2% belonged to lysis group II.
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