In vivo antibacterial activity and pharmacological properties of the membrane-active glycopeptide antibiotic YV11455.

The membrane-active glycopeptide antibiotic YV11455 is a lipophilic cationic vancomycin analogue that demonstrates rapid and concentration-dependent killing of clinically relevant multidrug-resistant (MDR) Gram-positive bacteria in vitro. YV11455 was 2-fold and 54-270-fold more effective than vancomycin against clinical isolates of vancomycin-sensitive and vancomycin-resistant bacteria, respectively. In this study, the in vivo efficacy, pharmacodynamics, pharmacokinetics and acute toxicology of YV11455 were investigated. In vivo activity and pharmacodynamics were determined in the neutropenic mouse thigh infection model against meticillin-resistant Staphylococcus aureus (MRSA). YV11455 produced dose-dependent reductions in MRSA titres in thigh muscle. When administered intravenously, the 50% effective dose (ED(50)) for YV11455 against MRSA was found to be 3.3 mg/kg body weight, and titres were reduced by up to ca. 3log(10)CFU/g from pre-treatment values at a dosage of 12 mg/kg with single treatment. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged half-life, with an increase in drug exposure (area under the concentration-time curve) compared with vancomycin. The peak plasma concentration following an intravenous dose of 12 mg/kg was 543.5 µg/mL. Acute toxicology studies revealed that YV11455 did not cause any significant alterations in biochemical parameters or histological pictures related to major organs such as the liver and kidney at its pharmacodynamic endpoint (ED(3-log kill)). These findings collectively suggest that YV11455 could be used clinically for the treatment of infections caused by MDR Gram-positive bacteria.

Novel quadruple mutations in dihydropteroate synthase genes of Plasmodium falciparum in West Bengal, India.

OBJECTIVE: To evaluate the anti-folate (sulphadoxine)-resistant pattern in Kolkata, one of the malaria endemic zones of Eastern India. METHODS: At first, 107 P. falciparum suspected cases were enrolled in this study. Ninety isolates (84.11%) of 107 suspected cases were analysed, as they had mono-infection with P. falciparum. In vitro susceptibility assays were performed in all 90 isolates. Parasitic DNA was isolated by phenol-chloroform extraction method and polymerase chain reaction was followed by restriction fragment length polymorphism analysis of different codons of the pfdhps gene (436, 437, 540, 581 and 613). RESULTS: Among 90 isolates from Kolkata, dhps mutant isolates at codons 436, 437, 540, 581 and 613 were found in 53.33%, 67.78%, 46.66%, 15.56% and 45.55%, respectively. In vitro sulphadoxine resistance was found in 49 isolates (54.44%). Interestingly we found 33 isolates (36.67%) with quadruple AGEAT mutant allele, of which 32 isolates (96.97%) were highly sulphadoxine resistant (P < 0.01) in vitro. CONCLUSION: Our present findings implicate that because of enormous drug (sulphfadoxine) pressure, novel AGEAT mutation was highly correlated (P < 0.01) with sulphadoxine resistance.