Bactericidal Activity of Moxifloxacin on Exponential and Stationary Phase Cultures ofMycobacterium tuberculosis

Abstract

The bactericidal activity of moxifloxacin, alone and in combination with isoniazid and rifampin, was studied on exponential and stationary phase cultures of Mycobacterium tuberculosis H37 Rv strain, the standard strain which is a wild type of M. tuberculosis strain, not exposed to any environment, susceptible to all anti-tuberculosis drugs. Moxifloxacin alone was highly bactericidal, being intermediate in activity between isoniazid and rifampin on both types of culture. The speed of activity was slow with the stationary phase culture, causing a reduction from 6.41 log(10)cfu/ml to 2.70 log(10)cfu/ml on day 6 with the higher moxifloxacin concentration of 4 microg/ml and to 4.08 log(10)cfu/ml with the lower concentration of 0.25 microg/ml. When added to isoniazid, its activity against both exponential and stationary phase cultures was increased. However, when it was added to rifampin, no increase in activity was found with either type of culture. Addition of moxifloxacin to isoniazid and rifampin resulted in a slight increase in activity against the exponential culture but a considerable increase against the stationary culture with counts below the limit of detection at 4 and 6 days with both moxifloxacin concentrations. The synergism found with isoniazid, but not with rifampin, supports the view that isoniazid should be included in combinations with moxifloxacin during the therapy of pulmonary tuberculosis.

Docking studies on novel analogues of 8 methoxy fluoroquinolones against GyrA mutants of Mycobacterium tuberculosis

“…The docking scores confirmed our earlier in vitro studies that moxifloxacin had a better killing activity than gatifloxacin against Mycobacterium tuberculosis H37 Rv [20,21]. The docking studies also yielded that increase in the lipophilicity on either of the positions of the quinolone structure considerably increased the binding affinities.…”

“…These resistant strains showed high sensitivity to both moxifloxacin and gatifloxacin (Figure 6). Our earlier in vitro findings on actively growing and persister Mycobacterium tuberculosis H37 Rv, showed that moxifloxacin is considered to have good sterilizing activity in addition to early bactericidal activity [20]. This could be correlated with the higher binding affinity calculated between the mutant and wild type Gyr A receptors and moxifloxacin (-7.9 kcal/mol) when compared to the maximum binding affinity output from gatifloxacin (-7.4 kcal/mol) (Table 1).…”

“…In order to improve the binding affinity, two different modifications on the 'Antibacterial spectrum' determining region and 'DNA gyrase binding' region, as described by Emami et al , [20] were attempted in the structures of GFX and MFX. The analogues are listed in Additional file 1, Figure S1.…”

“…This could be correlated with the higher binding affinity calculated between the mutant and wild type Gyr A receptors and moxifloxacin (-7.9 kcal/mol) when compared to the maximum binding affinity output from gatifloxacin (-7.4 kcal/mol) (Table 1). This could also be extended to the observation that although gatifloxacin exhibited good bactericidal activity against multiplying organisms it had very limited sterilizing activity against persisters [20]. …”

“…The developed ligands using the ChemSketch tool were based on the structures of GFX (Figure 1B) and MFX (Figure 1C) since these drugs have better activity, both in vitro [20,21] and in vivo against MDR-TB [22]. Various modifications in the 'Antibacterial spectrum' determining region and 'DNA gyrase binding' region of the fluoroquinolone as mentioned by Emami et al , [23].…”