Mycobacterium tuberculosis gyrase inhibitors as a new class of antitubercular drugs

Abstract

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.

FIG 1

Structures of the best balanced NBTI/MGI hits.

FIG 2

Time-kill curves of M. tuberculosis H37Rv in 7H9ADC medium at 20× MIC of compounds 2 and 3. Linezolid was used as a bacteriostatic model drug while isoniazid and a GSK InhA direct inhibitor were used as bactericidal controls.

FIG 3

Mapping of resistance mutations in the GyrA-GyrB model from M. tuberculosis. The M. tuberculosis gyrase A homology model was built using the S. aureus X-ray structure (PDB code 2XCS).

FIG 4

Plot of the concentration-dependent inhibitory effect of a representation of MGIs and NBTIs against M. tuberculosis DNA gyrase expressed as pIC₅₀ versus H37Rv MIC (μM). Compounds 1, 2, and 3 are indicated as black squares.

FIG 5

Antitubercular activity of isoniazid, moxifloxacin, and compounds 1, 2, and 3 in an acute infection murine model. Each circle represents data from an individual mouse. *, a P value of >0.05 was considered significant. Data were analyzed by a one-factor analysis of variance (ANOVA) and a Games-Howell post hoc test, since the P value for the Levene test was <0.05.