Comparative efficacy of novobiocin and amoxicillin in experimental sepsis caused by β-lactam-susceptible and highly resistant pneumococci

Revisiting aminocoumarins for the treatment of melioidosis

“…It was found that while novobiocin reached a peak concentration of 10 739 nM, coumermycin peaked at 102 767 nM and also had a significantly longer half-life in plasma (5.9 h vs. 2.8 h) ( Table 1 ). The half-life values are similar to those reported by others [ 10 , 22 ], whilst the plasma concentrations for coumermycin are substantially higher than in studies that used a subcutaneous rather than intraperitoneal injection route [23] , even accounting for differences in treatment dose. The relatively low plasma concentration of novobiocin may explain its loss of activity in vivo since the unbound (free) drug available is likely to be less than the threshold required to inhibit topoisomerase and gyrase [13] .…”

“…2 ). Whilst some mild toxicity including skin rash and nausea has been reported with the use of novobiocin, other reports suggest that it is in fact generally well tolerated and that impurities in the formulation may instead be responsible for such side effects [10] . In the present study, no toxicity was observed at the dosage of coumermycin used in the murine experiments.…”

“…Since coumermycin was highly active in the Galleria screen and showed enhanced pharmacokinetics over novobiocin, this compound was selected as the test aminocoumarin for treatment of melioidosis in an acute murine model of infection [24] . Novobiocin has previously shown potential in the treatment of sepsis caused by Streptococcus pneumoniae [10] . Since formulation with l -tyrosine enhanced the in vivo activity of novobiocin, we reasoned that it may similarly enhance the potency of coumermycin.…”

“…Antimicrobial resistance among many pathogens is a legitimate concern. Success in this regard has been reported by utilising novobiocin combined with rifampicin in a dual-therapy approach that mitigates drug resistance [10] . Novel related antibiotics such as kibdelomycin are also effective against strains of bacteria that are otherwise resistant to aminocoumarins or quinolones [26] .…”

“…Aminocoumarins, which include novobiocin, coumermycin and clorobiocin, are a class of antibiotics that target the ATPase activity of the GyrB subunit of DNA gyrase and the ParE subunit of topoisomerase IV, disrupting DNA replication and transcription. They bind gyrase with greater affinity than quinolones, which target the GyrA subunit, and they additionally prevent ATP binding [10] .…”