PubMed · 1919447
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K C Johnson, R H Joe, T H Self. 1991. Drug interaction.. https://pubmed.ncbi.nlm.nih.gov/1919447/
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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.
The X-ray structure analysis of the title compound, chloro[1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-4-ium-1-yl)-3-quinolinecarboxylate-kappa(2)O(3),O(4)](1,10-phenanthroline-kappa(2)N,N')copper chloride dihydrate, [CuCl(C(17)H(18)FN(3)O(3))(C(12)H(8)N(2))]Cl x 2H(2)O or [CuCl(cfH)(phen)]Cl x 2H(2)O, where cfH is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-4-ium-1-yl)-3-quinolinecarboxylate and phen is 1,10-phenanthroline, shows that the geometry around the Cu ion is a slightly distorted square pyramid. Two O atoms of the carbonyl and carboxyl groups of ciprofloxacin and two N atoms of 1,10-phenanthroline are coordinated to the metal centre in the equatorial plane, and a Cl(-) ion is coordinated at the apical position. Extensive intermolecular hydrogen bonding produces a supramolecular structure that consists of alternating six- and 12-membered rings.
Recently, in situ gel formation has extensively been studied to enhance ocular bioavailability and duration of the drug activity. In this study, we report grafting of poloxamer onto the hyaluronic acid for application of tissue engineering oriented ophthalmic drug delivery system. Graft copolymers were prepared by coupling mono amine-terminated poloxamer (MATP) with hyaluronic acid (HA) backbone using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and N-hydroxylsuccinimide (NHS) as coupling agents. The coupling of MATP with HA was clarified by 1H NMR and FT-IR spectroscopy. The gelation temperature of graft copolymers was dependent on the content of HA and the concentration of poloxamer. From drug release studies in vitro, ciprofloxacin was sustainedly released from the poloxamer-g-hyaluronic acid hydrogel due to the in situ gel formation of the copolymer and viscous properties of HA.