The following are the supplementary data related to

The following are the supplementary data related to this article.
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Introduction Although most of the drugs for tuberculosis were discovered >50years ago, TB accounts for about 1.4 million deaths every year (Zumla et al., 2013). The majority of the TB cases are treatable with the current long and complex regimen of drugs, although the lack of adherence due to adverse effect is not unusual, leading to suboptimal responses and rising incidences of M(X)DR cases worldwide. In the last 40years, only two new drugs have been approved for the treatment of MDR-TB under specific conditions: bedaquiline and delamanid (Andries et al., 2005; Thakare et al., 2015). Thus, there is a critical need for the development of drugs with shorter, simpler regimens as well as novel mechanisms of action that can be used for treatment of drug-resistant forms of the disease. Both target-based (Makarov et al., 2009) and phenotypic screening (Ballell et al., 2013; Lechartier et al., 2014; Mak et al., 2012; Pethe et al., 2010) approaches have been employed for the identification of antitubercular drug leads. While a limited but significant number of examples exist for the latter (Abrahams et al., 2012; Makarov et al., 2009; Remuinan et al., 2013), target-based approaches have encountered very limited success as previously demonstrated in the antibacterial field (Abrahams et al., 2012; Payne et al., 2007). Rather than invalidating the approach per se, this situation highlights the disconnection between concepts like genetic validation of target essentiality and the amenability of that target for drug discovery. A deeper understanding of system biology and the mechanisms underlying antibiotic killing are important for the discovery of new antimicrobial therapies through target-based approaches. Additionally, for reasons that are not always obvious, some targets are clearly more chemically tractable than others. For example, protein and Angiogenesis Compound Library bio-synthesis and DNA gyrase have delivered multiple classes of published leads and marketed drugs, whereas there are no known inhibitors for many other essential gene products, despite a long history of antibacterial research (Kohanski et al., 2010). In the antitubercular field, only a very limited number of targets such as InhA, RpoB, DNA Gyrase, ATP synthase, and DprE1 have been shown to be behind the action of potent bactericidal drugs or promising leads. Isoniazid is a frontline anti-TB drug targeting InhA and is an essential component of TB treatment regimen. Despite the seemingly simple structure of INH, its mode of action has remained elusive for many years (Vilcheze and Jacobs, 2007). INH penetrates the tubercle bacilli by passive diffusion and is activated by the bacterial anti-oxidant enzyme KatG to a range of reactive species and isonicotinic acid. Relevant reactive species form adducts with nicotinamide adenine dinucleotide (NAD), which are able to interfere with NAD-utilizing enzymes, primarily the enoyl-ACP reductase encoded by the inhA gene, leading to the blockage of mycolic acid synthesis and delivering the lethal blow to M. tuberculosis. The dependency on KatG activation for INH-mediated killing is also the source of the main clinical weakness associated with the use of INH, as between 40% and 95% of INH-resistant MTB clinical isolates have mutations in katG, leading to decreased activation of INH to its active form (Hazbon et al., 2006; Seifert et al., 2015). While mutations are also detected in clinical isolates in the inhA promoter region, these can be successfully treated in most instances by increasing the dose of isoniazid. Different classes of direct InhA inhibitors have been identified previously using high-throughput screening, Encoded Library Technology, and in silico design strategies (Lu et al., 2010; Manjunatha et al., 2015; Pan and Tonge, 2012; Shirude et al., 2013; Sink et al., 2015; Vilcheze et al., 2011; Encinas et al., 2014). Additionally, natural product pyridomycin has been found to operate via InhA inhibition (Hartkoorn et al., 2012; Lu et al., 2010). Most of these tended to show a lack of correlation between enzymatic inhibition and whole-cell activity, have moderate potencies, narrow selectivity windows or poor absorption, distribution, metabolism, and excretion (ADME) properties, making them unsuitable for further progression as drug leads.