Pathogenic mycobacteria are among the most devastating infectious agents of mortality worldwide causing tuberculosis, opportunistic infections of AIDS patients, and leprosy. A major problem in controlling mycobacterial infections is their remarkable antibiotic tolerance that limits chemotherapeutic options and is the root cause of treatment failure. In addition, pathogenic mycobacteria are able to persist for a long period of time inside the host cells circumventing host destruction. Persistence and antibiotic resistance are phenotypically associated and are supported by related genetic or physiological determinants.
We are studying mechanisms involved in intrinsic antibiotic resistance, persistence/virulence and how they are connected in pathogenic mycobacteria. Understanding these mechanisms may help develop novel antimycobacterial drugs that overcome the inherent antibiotic resistance and latent infection of pathogenic mycobacteria.
Figure legend: The triangle of interactions among pathogenic mycobacteria, host responses, and drugs that are used to treat the diseases. Although the pairwise interactions between mycobacteria, host defenses, and antimicrobial reagents have been studied at some levels, other more complex interactions [e.g., effects of antibiotics on host-mycobacterial interactions, effects of host responses on antibiotic activity and resistance (question marks)] are still elusive and need further investigation.
Wolff K, de la Peņa AH, Nguyen H, Pham T, Amzel M, Gabelli SB, and Nguyen L. 2015. A Redox Regulatory System Critical for Mycobacterial Survival in Macrophages and Biofilm Development. PLoS Pathogens. 11(4): e1004839. doi:10.1371/journal.ppat.1004839 [PubMed]
Ogwang S, Nguyen H, Sherman S, Bajaksouzian S, Jacobs MR, Boom WH, Zhang GF, and Nguyen L. (2011) Bacterial conversion of folinic acid is required for antifolate resistance. J Biol Chem. 286: 15377-90. [PubMed]
Nguyen HT, Wolff KA, Cartabuke RH, Ogwang S & Nguyen L. (2010) A lipoprotein modulates activity of the MtrAB two-component system to provide intrinsic multidrug resistance, cytokinetic control and cell wall homeostasis in Mycobacterium. Mol Microbiol 76, 348-364. [PubMed]
Scherr N & Nguyen L. (2009). Mycobacterium versus Streptomyces: We are different, we are the same. Curr Opin Microbiol 12, 699-707. [PubMed]
Wolff KA, Nguyen HT, Cartabuke RH, Singh A, Ogwang S & Nguyen L. (2009) Protein kinase G is required for intrinsic antibiotic resistance in mycobacteria. Antimicrob Agents Chemother 53, 3515-9. [PubMed]
Nguyen L & Pieters J. (2009) Mycobacterial subversion of chemotherapeutic reagents and host defense tactics: challenges in tuberculosis drug development. Annu Rev Pharmacol Toxicol. 49, 427-453. [PubMed]
Nguyen L, Scherr N, Gatfield J, Walburger A et al. (2007) Antigen 84, an effector of pleiomorphism in Mycobacterium smegmatis. J Bacteriol 189, 7896-910 [PubMed]
Nguyen L, Chinnapapagari S & Thompson CJ. (2005) FbpA-Dependent biosynthesis of trehalose dimycolate is required for the intrinsic multidrug resistance, cell wall structure, and colonial morphology of Mycobacterium smegmatis. J Bacteriol. 187, 6603-6611. . [PubMed]
Walburger A, Koul A, Ferrari G, Nguyen L et al. (2004) Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science. 304, 1800-1804. [PubMed]
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