DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.

The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg−1 and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4–5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.

Moxifloxacin has shown excellent activity against drug-sensitive as well as drug-resistant tuberculosis (TB), thus confirming DNA gyrase as a clinically validated target for discovering novel anti-TB agents. We have identified novel inhibitors in the pyrrolamide class which kill Mycobacterium tuberculosis through inhibition of ATPase activity catalyzed by the GyrB domain of DNA gyrase. A homology model of the M. tuberculosis H37Rv GyrB domain was used for deciphering the structure-activity relationship and binding interactions of inhibitors with mycobacterial GyrB enzyme. Proposed binding interactions were later confirmed through cocrystal structure studies with the Mycobacterium smegmatis GyrB ATPase domain. The most potent compound in this series inhibited supercoiling activity of DNA gyrase with a 50% inhibitory concentration (IC 50 ) of <5 nM, an MIC of 0.03 g/ml against M. tuberculosis H37Rv, and an MIC 90 of <0.25 g/ml against 99 drug-resistant clinical isolates of M. tuberculosis. The frequency of isolating spontaneous resistant mutants was ϳ10 ؊6 to 10 ؊8 , and the point mutation mapped to the M. tuberculosis GyrB domain (Ser208 Ala), thus confirming its mode of action. The best compound tested for in vivo efficacy in the mouse model showed a 1.1-log reduction in lung CFU in the acute model and a 0.7-log reduction in the chronic model. This class of GyrB inhibitors could be developed as novel anti-TB agents. In 2010, the World Health Organization estimated that ϳ11.1 million people across the globe were infected with Mycobacterium tuberculosis, with an associated mortality rate of 1.3 million (1). Patients with drug-sensitive tuberculosis (TB) are treated with an intensive regimen consisting of a 2-month, once-daily combination therapy of isoniazid, rifampin, pyrazinamide, and ethambutol. This is followed by a 4-month continuation regimen with isoniazid and rifampin (2).These anti-TB drugs were discovered in the period spanning 1945 to 1965. The reemergence of TB due to HIV and multiple-drug-resistant (MDR) strains of TB has created a global epidemic. Therefore, there is an urgent need to discover new drugs with a novel mode of action (3-6).The clinical efficacy of fluoroquinolone drugs demonstrated over the past 20 to 30 years has validated DNA gyrase as a target in the area of broad-spectrum antibacterials (7). DNA gyrase is essential for growth in all bacteria, including mycobacteria. Due to the absence of topoisomerase IV, DNA gyrase is essential for DNA supercoiling as well as decatenation activities in M. tuberculosis (8). In addition, this enzyme is essential for DNA replication and repair as well as transcription. Therefore, we believed that a novel class of DNA gyrase inhibitors would be effective anti-TB agents.DNA gyrase is a heterotetramer comprising of GyrA and GyrB subunits (A 2 B 2 ). GyrA contains the DNA breakage-reunion site, while GyrB hydrolyzes ATP (9). This enzyme introduces negative supercoils into circular DNA following ATP hydrolysis. DNA gyrase also catalyzes the interconversion...

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Structure-activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to potent antimycobacterial activity (Mtb MIC = 0.06 μM) against Mycobacterium tuberculosis (Mtb). Additionally, this knowledge provided a robust SAR understanding to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase and retains its antimycobacterial activity against moxifloxacin-resistant strains of Mtb. Finally, we demonstrate in vivo proof of concept in an acute mouse model of TB following oral administration of compound 19.