This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Philalay, J. S. Articles by Cangelosi, G. A. Search for Related Content PubMed PubMed Citation Articles by Philalay, J. S. Articles by Cangelosi, G. A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2004, p. 3412-3418, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3412-3418.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Genes Required for Intrinsic Multidrug Resistance in Mycobacterium avium

Seattle Biomedical Research Institute, Seattle, Washington

Received 12 February 2004/ Returned for modification 28 April 2004/ Accepted 8 May 2004

Genes required for intrinsic multidrug resistance by Mycobacterium avium were identified by screening a library of transposon insertion mutants for the inability to grow in the presence of ciprofloxacin, clarithromycin, and penicillin at subinhibitory concentrations. Two genes, pks12 and Maa2520, were disrupted in multiple drug-susceptible mutants. The pks12 gene (Maa1979), which may be cotranscribed with a downstream gene (Maa1980), is widely conserved in the actinomycetes. Its ortholog in Mycobacterium tuberculosis is a polyketide synthase required for the synthesis of dimycocerosyl phthiocerol, a major cell wall lipid. Mutants of M. avium with insertions into pks12 exhibited altered colony morphology and were drug susceptible, but they grew as well as the wild type did in vitro and intracellularly within THP-1 cells. A pks12 mutant of M. tuberculosis was moderately more susceptible to clarithromycin than was its parent strain; however, susceptibility to ciprofloxacin and penicillin was not altered. M. avium complex (MAC) and M. tuberculosis appear to have different genetic mechanisms for resisting the effects of these antibiotics, with pks12 playing a relatively more significant role in MAC. The second genetic locus identified in this study, Maa2520, is a conserved hypothetical gene with orthologs in M. tuberculosis and Mycobacterium leprae. It is immediately upstream of Maa2521, which may code for an exported protein. Mutants with insertions at this locus were susceptible to multiple antibiotics and slow growing in vitro and were unable to survive intracellularly within THP-1 cells. Like pks12 mutants, they exhibited increased Congo red binding, an indirect indication of cell wall modifications. Maa2520 and pks12 are the first genes to be linked by mutation to intrinsic drug resistance in MAC.

This article has been cited by other articles:

• Freeman, R., Geier, H., Weigel, K. M., Do, J., Ford, T. E., Cangelosi, G. A. (2006). Roles for Cell Wall Glycopeptidolipid in Surface Adherence and Planktonic Dispersal of Mycobacterium avium. Appl. Environ. Microbiol. 72: 7554-7558 [Abstract] [Full Text]  
• Cangelosi, G. A., Do, J. S., Freeman, R., Bennett, J. G., Semret, M., Behr, M. A. (2006). The Two-Component Regulatory System mtrAB Is Required for Morphotypic Multidrug Resistance in Mycobacterium avium. Antimicrob. Agents Chemother. 50: 461-468 [Abstract] [Full Text]  
• Bertram, R., Kostner, M., Muller, J., Ramos, J. V., Hillen, W. (2005). Integrative elements for Bacillus subtilis yielding tetracycline-dependent growth phenotypes. Nucleic Acids Res 33: e153-e153 [Abstract] [Full Text]