In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics

Abstract

Spectinamides are new semi-synthetic spectinomycin derivatives with potent anti-tubercular activity. The reported synergism of the precursor spectinomycin with other antibiotics prompted us to examine whether spectinamides sensitize M. tuberculosis to other antibiotics not traditionally used in the treatment of tuberculosis to potentially expand therapeutic options for MDR/XDR Tuberculosis. Whole cell synergy checkerboard screens were performed using the laboratory strain M. tuberculosis H37Rv, lead spectinamide 1599, and a broad panel of 27 antibiotics. In vitro, 1599 synergized with 11 drugs from 6 antibiotic classes. The observed synergy was tested against clinical isolates confirming synergy with Clarithromycin, Doxycycline and Clindamycin, combinations of which were taken forward for in vivo efficacy determination. Co-administration of 1599 and clarithromycin provided additional bacterial killing in a mouse model of acute tuberculosis infection, but not in a chronic infection model. Further studies indicated that mismatched drug exposure profiles likely permitted induction of phenotypic clarithromycin resistance and subsequent loss of synergism. These studies highlight the importance of validating in vitro synergism and the challenge of matching drug exposures to obtain a synergistic outcome in vivo. Results from this study indicate that a 1599 clarithromycin combination is potentially viable, providing the drug exposures can be carefully monitored.

Antibacterial fatty acids destabilize hydrophobic and multicellular aggregates of biofilm in S. aureus

“…Otherwise, low doses of antibiotic may permit induction of resistance mechanisms (for example, subinhibitory concentrations of clarithromycin) and induces clarithromycin resistance in Mycobacterium tuberculosis in vivo. 31 The other major characteristic was noticed in terms of FAME production by planktonic cells and biofilm indwellers. FAMEs are extracellular enzymes produced by S. aureus and S. epidermidis, responsible for inactivation of bactericidal fatty acids by esterifying them to cholesterol.…”

“…This suggests that improper use of antibiotics may result in induction of resistant bacteria. Bruhn et al 31 suggested that, after administration, antibiotic must reach the bloodstream and tissues in sufficient concentrations required for bacterial killing. Otherwise, low doses of antibiotic may permit induction of resistance mechanisms (for example, subinhibitory concentrations of clarithromycin) and induces clarithromycin resistance in Mycobacterium tuberculosis in vivo.…”

Cooperation of Doxycycline with Phytochemicals and Micronutrients Against Active and Persistent Forms of Borrelia sp

“…They noticed synergy with clarithromycin, doxycycline and clindamycin against clinical isolates. Further in vivo study of the efficacy of these combinations documented additional bacterial killing effect in a mouse model of acute tuberculosis infection, but not in a chronic infection model 62. In the study of Gonzalo, et al , amikacin in combination with doxycycline tested against clinical strains of Mycobacterium tuberculosis showed a synergistic effect in 18 of the 29 strains, and indifference in 11 strains 63.…”

Anti-Dysentery Activity of Tetracycline in Combination With Curcuma Xanthorrhiza Roxb. Or Sonchus Arvensis L.

“…Although it is known that to achieve synergism in vivo, sufficient concentration of antibiotics in the bloodstream and infected tissues are important. The concentration of single drug of drug combinations is needed to have a longer half-life to prevent the induction of transient resistance mechanisms and the selection of genetic mutants [14]. Therefore, the pharmacokinetic profile of plant extract is needed for further study.…”