The mycobacterial antigens 85 complex – from structure to function and beyond: Response

We take a much more optimistic view of the potential of the antigens 85 complex as a target for the development of new antimycobacterial drugs and vaccines. The crystal structure of antigen 85C provides proof that antigens 85A, B and C all have nearly identical active sites, and that they are very different from any human protein identified to date. In fact, we know of no pathways in humans that process any compounds chemically similar to trehalose monomycolate or trehalose dimycolate, the substrates of the antigen 85 proteins. Pharmaceutical companies have already demonstrated many times their ability to build specificity into inhibitors. For example, inhibitors for HIV protease over human renin, both aspartyl proteases, are being used to treat AIDS, and non-steroidal anti-inflammatory drugs (NSAIDS) that show specificity for cyclooxygenase 2 over cyclooxygenase 1 are available. Therefore, it seems unlikely that the design of inhibitors specific for the antigen 85 proteins will be a major problem.Dr Daffe's own work supports the crucial nature of the antigens 85 enzyme complex to Mycobacterium tuberculosis1. They have demonstrated that mycobacteria in which antigen 85C is missing show a 40% decrease in cell-wall-linked mycolic acids. No reports of multiple knockouts of antigen 85A, B, or C have appeared in the literature, suggesting that such knockouts could be lethal. We therefore agree with Dr Daffe's own words from his 1999 paper in Molecular Microbiology:‘…from the results presented here, it is established that a 40% decrease of the cell wall-bound mycolate content does not affect M. tuberculosis extra- and intracellular growth. Thus, our data point out the necessity for an anti-mycobacterial drug directed against the antigens 85 to target at least two of these proteins because the disruption of only the antigen 85C gene is not sufficient to affect M. tuberculosis survival.’[1xInactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope. Jackson, M. et al. Mol. Microbiol. 1999; 31: 1573–1587Crossref | PubMed | Scopus (164)See all References[1]The antigens 85 complex is clearly a major antigen in the humoral response to M. tuberculosis infection, and protective immunity after vaccination with antigen 85A or B has been demonstrated in the guinea-pig model system[[2]xProtective immunity against tuberculosis induced by vaccination with major extracellular proteins of Mycobacterium tuberculosis. Horwitz, M.A. et al. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1530–1534Crossref | PubMed | Scopus (375)See all References, [3]xEvaluation of new vaccines in the mouse and guinea pig model of tuberculosis. Baldwin, S.L. Infect. Immun. 1998; 66: 2951–2959PubMedSee all References]. The antigens 85 complex is also involved in the complement-mediated endocytotic pathway, which stimulates uptake of the bacteria into the macrophage[4xPhagocytosis of Mycobacterium leprae by human monocyte-derived macrophages is mediated by complement receptors CR1 (CD35), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) and IFN-γ activation inhibits complement receptor function and phagocytosis of this bacterium. Schlesinger, L.S. and Horwitz, M.A. J. Immunol. 1991; 147: 1983–1994PubMedSee all References[4]. Although there are a number of reports of alternative pathways for uptake, we know of no data that quantify which pathways are essential for disease. To say that the antigens 85 complex has no value as a vaccine candidate is premature.Unfortunately, Dr Daffe's conclusion that our work is an academic pursuit could be correct, although his reasons are not. The lack of interest in developing new drugs to treat tuberculosis by major pharmaceutical companies is probably a more accurate reason why this work and the work of others will remain in the academic world.