Protein splicing inhibitors as a new class of anti mycobacterial agents

The alarming worldwide increase in multicirug-resistant and extensively drug-resistant tuberculosis (TB) calls for new anti mycobacterial drugs against new types of targets which are less likely to undergo mutations that lead to drug resistance. The discovery that three genes of Mycobacterium tuberculosis, recA, dnaB and sufB, are interrupted by inteins, which must be excised from inactive precursor proteins by the process of protein splicing to yield functional proteins, suggests protein splicing as a novel target for anti-TB drugs. Since two of these genes are essential for growth and the third predisposes to drug resistance mutations, protein splicing inhibitors, which disable two separate vital functions and at the same time suppress mutation rates, would be unlikely to elicit drug resistance. A robust, protein-based high-throughput screening system for protein splicing inhibitors has been developed and used for screening small-molecule compound libraries, leading to more than 50 confirmed positives with IC50 values in the low micromolar range. Most of the confirmed protein splicing inhibitors are electrophiles that inhibit protein splicing irreversibly by binding to the catalytic cysteine residue. Lead optimization, aided by docking to the known crystal structure of the RecA intein, should yield a valuable new class of antimycobacterial drugs for the treatment of drug-resistant TB.