*3.2. Beta Lactams as Antimycobacterials*

Several broad-spectrum antibacterials like meropenem, a beta-lactam, have also been shown to have activity against MTB in in vitro models, as well as in studies measuring Early Bactericidal Activity (EBA) in humans [36].

The key 'unknowns' in the development of broad-spectrum antibiotics as anti-TB treatment are twofold:


Despite these concerns, even after several years of the use of rifampicin for the treatment of Drug sensitive (DS) TB and moxifloxacin for the treatment of MDR TB, the extent of 'priming' caused is not clear, and some of the fears could well be unfounded. This could also be a reflection of the use of these drugs only in combinations or our inability to monitor the impact systematically.

The key learning from this approach of including broad-spectrum antibiotics into the combination regimen to treat MTB patients has been as follows:


**Figure 2.** Two novel compounds that have entered clinical development (**a**) GSK070 and (**b**) SPR20.

#### *3.3. Gyrase Inhibitors*

The fluoroquinolone class (Moxifloxacin, Levofloxacin, Ofloxacin, and Gatifloxacin) of compounds are potent inhibitors of the DNA gyrase enzyme and are proven antibacterials. Several of these were shown to be active on the MTB bacilli in vitro. Researchers at the National Tuberculosis Institute, India, tested the usefulness of ofloxacin as a part of the anti-TB regimen and showed it to be effective in the clinical trial [41]. Multiple members of this class of compounds have undergone clinical trials as part of an anti-TB regimen; moxifloxacin [42] is now a part of the standard regimen to treat drug-resistant TB infections. Section 3.4 covers the target-based TB drug discovery efforts at AstraZeneca, with major emphasis on gyrase inhibitors.
