A series of novel pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by the agar dilution method and Oxford cup assay. The majority of the tested compounds displayed moderate antibacterial activities. Importantly, the three compounds with amino or tertiary amine groups in their side chains, 11, 13b, and 15c, were the most active antibacterial agents. Docking experiments carried out on the peptidyl transferase center (PTC) of 23S rRNA proved that there is a reasonable direct correlation between the binding free energy (ΔGb, kcal/mol) and the antibacterial activity. Moreover, the pharmacokinetic profiles of 11 and 15c in rat were characterized by moderate clearance and oral bioavailability.

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Isoniazid (INH) and ethambutol (EMB) are two major first-line drugs for managing tuberculosis (TB), caused by the microbe Although co-use of these two drugs is common in clinical practice, the mechanism for the potential synergistic interplay between them remains unclear. Here, we present first evidence that INH and EMB act synergistically through a transcriptional repressor of the gene, the target gene of INH encoding an enoyl-acyl carrier protein reductase of the fatty acid synthase type II system required for bacterial cell wall integrity. We report that EMB binds a hypothetical transcription factor encoded by the gene, designated here as EtbR. Using DNA footprinting, we found that EtbR specifically recognizes a motif sequence in the upstream region of the gene. Using isothermal titration calorimetry and surface plasmon resonance assays, we observed that EMB binds EtbR in a 1:1 ratio and thereby stimulates its DNA-binding activity. When a nonlethal dose of EMB was delivered in combination with INH, EMB increased the INH susceptibility of cultured cells. In summary, EMB induces EtbR-mediated repression of and thereby enhances the mycobactericidal effect of INH. Our findings uncover a molecular mechanism for the synergistic activity of two important anti-TB drugs.