Effects of Lipid-Lowering Drugs on Vancomycin Susceptibility of Mycobacteria

Abstract

Tuberculosis is still a cause of major concern, partly due to the emergence of multidrug-resistant strains. New drugs are therefore needed. Vancomycin can target mycobacteria with cell envelope deficiency. In this study, we used a vancomycin susceptibility assay to detect drugs hampering lipid synthesis in Mycobacterium bovis BCG and in Mycobacterium tuberculosis. We tested three drugs already used to treat human obesity: tetrahydrolipstatin (THL), simvastatin, and fenofibrate. Only vancomycin and THL were able to synergize on M. bovis BCG and on M. tuberculosis, although mycobacteria could also be inhibited by simvastatin alone. Lipid analysis allowed us to identify several lipid modifications in M. tuberculosis H37Rv treated with those drugs. THL treatment mainly reduced the phthiocerol dimycocerosate (PDIM) content in the mycobacterial cell wall, providing an explanation for the synergy, since PDIM deficiency has been related to vancomycin susceptibility. Proteomic analysis suggested that bacteria treated with THL, in contrast to bacteria treated with simvastatin, tried to recover, inducing, among other reactions, lipid synthesis. The combination of THL and vancomycin should be considered a promising solution in developing new strategies to treat multidrug-resistant tuberculosis.

Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects vancomycin susceptibility

“…The fixed concentrations were 4-and 20-fold lower than the MIC a or MIC b , respectively. In agreement with the checkerboard method, synergy is reached when the FICI is < 0.5 [25].…”

“…Tubes were place at 37°C without shaking. Growth or absence of growth was recorded on the day that the growth of the 100-fold diluted drug-free inoculum control became visible in order to assess the minimal inhibitory concentration of the drugs (MIC, being the lowest drug concentration inhibiting more than 99% of M. bovis BCG strain bacterial growth) [25]. This experiment was performed three times to check the reproducibility of the MIC determination.…”

“…As PDIM deficient M. bovis BCG and M. tuberculosis mutants are specifically more susceptible to vancomycin [8,25], by a 100-fold factor, we assessed the effect of MAFP on M. bovis BCG vancomycin susceptibility. MAFP increased by more than 10-fold the susceptibility of M. bovis BCG to vancomycin ( Table 2).…”

Visualization of mycobacterial membrane dynamics in live cells

“…48 These observations argue that more high-throughput screens against Mtb should be performed in the presence of a mycomembrane-compromising agent such as ethambutol. 44,49−52 …”

Esx Systems and the Mycobacterial Cell Envelope: What's the Connection?

“…Both mycobacteria and diderm-LPS bacteria are intrinsically resistant to several antibiotics, including the large hydrophilic glycopeptide vancomycin (122,123). Consistent with the idea that mycobacterial lipids provide a permeability barrier, mycobacterial strains lacking PDIM have increased susceptibility to vancomycin (124,125).…”