Proposed mechanism for generation of mycolic acid sub-types by the action of CMAS enzymes (A) and inhibition by TAC/SRI-224 (B).

<p>The generation of α- and the oxygenated mycolic acids is considered to follow to two independent pathways. A common, di-unsaturated precursor, Y, is envisaged for the two pathways. Y is subsequently transformed into α-mycolic acids by the action of the MmaA2 and PcaA that modify the distal or proximal double bond, respectively. Action of MmaA4 commits Y to the pathway for the oxygenated mycolic acids, by producing the precursor X. MmaA3, which is required for generation of methoxy-mycolic acids in <i>M. tb</i> is inactive in <i>M. bovis</i> BCG Pasteur due to the presence of a point mutation <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001343#pone.0001343-Behr1" target="_blank">[50]</a>. The proximal double bond is modified by the CmaA2 (and MmaA2) or PcaA to generate <i>trans</i>- or <i>cis</i>-cyclopropanated derivatives, respectively. In the presence of TAC, all the CMASs mentioned above are inhibited, except for MmaA4. Due to inhibition of MmaA2, excess of Y is diverted to MmaA4 leading to generation of X, which accumulates due to lack of activities of CmaA2 and MmaA2. SRI-224 appears to affect MmaA4 to a certain degree, leading to accumulation Y in addition to X. (For simplicity, only the meromycolyl moiety of mycolates has been depicted).</p>