The cornerstones of prophylaxis and treatment of infections caused by non-tuberculosis mycobacteria (NTM) are the macrolides, clarithromycin and azithromycin. Although clinically acquired macrolide resistance in mycobacteria is conferred by 23S rRNA gene mutation, intrinsic resistance involves expression of adenine rRNA methylases, or erm genes. Moreover, recent data indicates that other genes can significantly affect the antimycobacterial activity of macrolides. For instance, an rpsA gene allele confers high-level macrolide resistance, and evidence suggests that disruption of trans-translation increases the bactericidal activity of macrolides. In addition, Mycobacteria may have a macrolide efflux system. Therefore, we hypothesize that mycobacteria may have several mechanisms that reduce the antimicrobial effects of macrolides. These mechanisms may include target modification (e.g., rRNA methylation or mutation), target recovery (e.g., trans-translation), and drug transport (e.g., efflux). Consequently, the long-term objective of this work is to characterize the mechanisms that affect the susceptibility of mycobacteria to macrolides. To address this objective, the project is divided into 4 specific aims: (1) to characterize the erm genes of mycobacteria;(2) to correlate the function of the rpsA and smpB genes with resistance to and recovery from the affects of macrolides;(3) to characterize the putative membrane protein genes that affect susceptibility to macrolides;and (4) to define the distribution of genes that affect the activity of macrolides within the Mycobacteriaceae. Mycobacteria are important human pathogens that cause chronic, often intractable disease. Understanding resistance and other processes that reduce drug activity will aid the design and development of new agents with activity against mycobacteria and/or treatment regimens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052291-05
Application #
7538376
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Lacourciere, Karen A
Project Start
2002-07-01
Project End
2010-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$275,625
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Andini, Nadya; Nash, Kevin A (2011) Expression of tmRNA in mycobacteria is increased by antimicrobial agents that target the ribosome. FEMS Microbiol Lett 322:172-9
Nash, Kevin A; Brown-Elliott, Barbara A; Wallace Jr, Richard J (2009) A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae. Antimicrob Agents Chemother 53:1367-76
Nash, Kevin A; Andini, Nadya; Zhang, Yansheng et al. (2006) Intrinsic macrolide resistance in rapidly growing mycobacteria. Antimicrob Agents Chemother 50:3476-8
Andini, Nadya; Nash, Kevin A (2006) Intrinsic macrolide resistance of the Mycobacterium tuberculosis complex is inducible. Antimicrob Agents Chemother 50:2560-2
Nash, Kevin A; Zhang, Yansheng; Brown-Elliott, Barbara A et al. (2005) Molecular basis of intrinsic macrolide resistance in clinical isolates of Mycobacterium fortuitum. J Antimicrob Chemother 55:170-7
Nash, Kevin A (2003) Intrinsic macrolide resistance in Mycobacterium smegmatis is conferred by a novel erm gene, erm(38). Antimicrob Agents Chemother 47:3053-60