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Summary High through put screening (HTS) was extensively used in attempts to discover new TB drugs from libraries of pure small molecule compounds many of which complied with the rule of five. Coupled with new methods for determining the target of lead compounds by resistance selection followed by genome sequencing, screening for growth inhibitors led to several recent reports of compounds linked to specific antitubercular targets. This systematic approach to drug discovery appears at present to select for small, hydrophobic molecules affecting the function of essential membrane proteins, for example DprE, MmpL3, AtpE, QcrB, and Pks13. All of these molecules possessed bactericidal activity in vitro . Mutations in GlpK were also selected with hydrophobic compounds identified by screening for growth inhibitors. The chemical properties of the compounds reported are considered in the context of uptake and possible mechanisms of inhibition of membrane bound targets based on other model systems (e.g. cardiovascular drugs affecting voltage-gated L-type calcium channels, daptomycin, telavancin, gramicidin S, and role of boundary lipids). The relationship between hydrophobicity, compound uptake, and mode of action are addressed. Compared to the average calculated logP for approved TB drugs of −1.0, the average for these hydrophobic compounds is 4.0 representing a major shift in hydrophobicity of 5 orders of magnitude. Furthermore several hydrophobic compounds in the Prestwick Chemical Library (FDA approved drugs) inhibit growth of M. tuberculosis at 10 μg/ml or less and have an average calculated logP of 5.7 signaling caution with respect to specificity. Key recommendations are made regarding follow-up of the hydrophobic leads recently discovered using phenotypic screening and target elucidation by genome sequencing. Consideration is also given to the properties of small molecule screening libraries, the types of molecules and targets recently discovered as antitubercular leads and compliance with the rule of 5.

There is an urgent need for the discovery and development of new antitubercular agents that target novel biochemical pathways and treat drug-resistant forms of the disease. One approach to addressing this need is through high-throughput screening of drug-like small molecule libraries against the whole bacterium in order to identify a variety of new, active scaffolds that will stimulate additional biological research and drug discovery. Through the Molecular Libraries Screening Center Network, the NIAID Tuberculosis Antimicrobial Acquisition and Coordinating Facility tested a 215,110-compound library against Mycobacterium tuberculosis strain H37Rv. A medicinal chemistry survey of the results from the screening campaign is reported herein.

There is an urgent need for the discovery and development of new antitubercular agents that target new biochemical pathways and treat drug resistant forms of the disease. One approach to addressing this need is through high-throughput screening of medicinally relevant libraries against the whole bacterium in order to discover a variety of new, active scaffolds that will stimulate new biological research and drug discovery. Through the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (www.taacf.org), a large, medicinally relevant chemical library was screened against M. tuberculosis strain H37Rv. The screening methods and a medicinal chemistry analysis of the results are reported herein.

Increasing multidrug resistance in Mycobacterium tuberculosis continues to diminish the number of effective drugs available for treatment of active tuberculosis. Although there are four new products (representing three new chemical classes) in clinical development, an active, robust pipeline of new chemical entities is critical to discovery of medicines to dramatically improve or shorten length of therapy via new mechanisms of action. In the absence of major pharmaceutical industry activity in tuberculosis drug development, the National Institute of Allergy and Infectious Diseases (NIAID) has supported the development of a high throughput screen for growth inhibitors of M. tuberculosis using a chemically diverse commercial library, a compound library available through the NIH Roadmap, Molecular Libraries Screening Center Network, and other compound sources. The rationale for these screens and suggested approaches for follow-up studies to identify compounds for advanced preclinical studies and as chemical probes of critical functions in M. tuberculosis, are discussed.