Abstract
The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) has hampered treatments for tuberculosis, which consequently now require novel agents to overcome such drug resistance. The genetically stable D-alanine–D-alanine ligase A (DdlA) has been deemed as an excellent therapeutic target for tuberculosis. In the present study, a competitive inhibitor (IMB-0283) of DdlA was obtained via high-throughput screening. The minimum inhibitory concentrations (MIC) of IMB-0283 for the standard and clinical drug-resistant Mtb strains ranged from 0.25 to 4.00 μg/mL, whereas the conventional inhibitor of DdlA, D-cycloserine (DCS), only inhibited the growth of the standard Mtb strain at 16 μg/mL. The lethal effect of IMB-0283 on Mtb was found to act intracellularly in a DdlA-dependent manner. Specifically, IMB-0283 prevented the synthesis of neonatal cell walls but did not damage mature cell walls. Compared with those of DCS, IMB-0283 exhibited lower cytotoxicity and a higher selective index (SI). At the same dosages of treatment, IMB-0283 reduced bacterial load (log CFU/mL) in an acute animal model from 5.58 to 4.40, while DCS did not yield any such treatment efficacy. Taken together, the lower cytotoxicity and more efficacious in vivo activity of IMB-0283 suggest that it is a promising lead compound for antituberculosis drug development.
Highlights
Tuberculosis (TB) is remains as a high-burden disease and has claimed millions of lives all over the world due to infections of Mycobacterium tuberculosis (Mtb)
The selection of a specific therapeutic target for high-throughput screening determines the output of lead compounds; FIGURE 5 | D-alanine–D-alanine ligase A (DdlA) is essential for Mtb growth and IMB-0283 inhibits Mtb growth in a DdlA-dependent manner
DCS, D-cycloserine; MIC, minimum inhibitory concentrations; SI, selective index which was calculated via TC50/MIC
Summary
Tuberculosis (TB) is remains as a high-burden disease and has claimed millions of lives all over the world due to infections of Mtb. Novel Inhibitor of Mtb DdlA drug-resistant Mtb infections, which require novel agents to overcome such drug resistance. Validating whether a therapeutic target with a novel mechanism is worthy of further drug discovery and development is difficult, time-consuming, and requires tremendous resources. To efficiently utilize limited resources, we aimed to leverage a known druggable target since several old drug targets have been previously recognized as promising candidates. Our selection criteria for such old druggable targets were as follows: (1) genetic stability of the target, which may lessen the probability of drug resistance; and (2) the present inhibitor of the target is restricted due to severe side effects but not drug resistance. It is necessary to exploit novel anti-TB compounds that target Mtb DdlA. A safe and low-toxicity inhibitor of DdlA was obtained with potent anti-TB activity both in vitro and in vivo
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