Abstract
SummaryTryptophan biosynthesis represents an important potential drug target for new anti-TB drugs. We identified a series of indole-4-carboxamides with potent antitubercular activity. In vitro, Mycobacterium tuberculosis (Mtb) acquired resistance to these compounds through three discrete mechanisms: (1) a decrease in drug metabolism via loss-of-function mutations in the amidase that hydrolyses these carboxamides, (2) an increased biosynthetic rate of tryptophan precursors via loss of allosteric feedback inhibition of anthranilate synthase (TrpE), and (3) mutation of tryptophan synthase (TrpAB) that decreased incorporation of 4-aminoindole into 4-aminotryptophan. Thus, these indole-4-carboxamides act as prodrugs of a tryptophan antimetabolite, 4-aminoindole.
Highlights
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to take its toll on humanity with about 7 million new infections and 1.5 million people succumbing to the disease in 2018 (WHO, 2020)
C1 was not toxic to J774 macrophages (Figure S1) and afforded a 1.5 log reduction in intracellular Mtb titer when tested in a murine macrophage model of infection (Figure 1C)
Spontaneous resistance was observed at frequencies that varied depending on the number of bacilli plated; that is, when 107 CFU was plated, the frequency of resistance (FoR) was ~3 3 10À6, whereas at higher cell densities (109 CFU), the FoR was ~3 3 10À8
Summary
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to take its toll on humanity with about 7 million new infections and 1.5 million people succumbing to the disease in 2018 (WHO, 2020). While the outlook looks dire with the rise of strains resistant to one or more of the clinically approved drugs for TB, several new compounds with novel targets have reached clinical trials (Libardo et al, 2018), and treatment shortening regimens are being developed (Lee et al, 2020), offering hope to patients. The rise of multidrug-resistant Mtb reflects a vast repertoire of mechanisms the bacillus deploys to subvert drug action—from target modification to drug efflux and degradation (Mabhula and Singh, 2019). A thorough understanding of a drug’s mechanism of action and the ways in which Mtb resist their cidal effects is paramount to developing nextgeneration antitubercular compounds. Tryptophan biosynthesis represents a promising pathway to target with novel drugs. Chorismate from the shikimate pathway is converted to L-tryptophan (L-Trp) in six enzymatic steps (Figure 1A). Anthranilate is converted to indole-3-glycerolphosphate by the actions of TrpD, TrpF, and
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