The Polyketide Synthase-Associated Multidrug Tolerance in Mycobacterium intracellulare Clinical Isolates

• Published in: Chemotherapy (Basel) Vol. 58; no. 5; pp. 341 - 348
• Main Authors: Matsunaga, Isamu, Meda, Shinji, Nakata, Noboru, Fujiwara, Nagatoshi
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2012
• Subjects: Anti-Bacterial Agents - pharmacology; Chemotherapy; Clinical outcomes; Drug resistance; Drug Resistance, Multiple, Bacterial - drug effects; Ethidium - chemistry; Humans; Microbial Sensitivity Tests; Microbiology; Mycobacterium avium Complex - drug effects; Mycobacterium avium Complex - enzymology; Mycobacterium avium Complex - isolation & purification; Mycobacterium avium-intracellulare Infection - microbiology; Mycobacterium bovis - drug effects; Mycobacterium bovis - enzymology; Mycobacterium bovis - isolation & purification; Pharmacology; Polyketide Synthases - genetics; Polyketide Synthases - metabolism; Polyketide synthase; Mycoketide; Mycobacterium intracellulare; Drug resistance
• ISSN: 0009-3157; 1421-9794
• DOI: 10.1159/000343311

Background: Intrinsic multidrug resistance of the Mycobacterium avium-intracellulare complex presents a serious problem in the treatment of the diseases caused by these bacteria. Recently, it was shown that deletion of a polyketide synthase, Pks12, in an M. avium laboratory strain decreases this intrinsic resistance. Methods: We investigated Pks12 expression and its enzymatic activity in 9 clinical isolates of M. intracellulare, and compared their drug susceptibilities to 4 drugs. Also, we made pks12-disrupted M. bovis bacillus Calmette-Guérin (BCG) mutant and its complemented strain. Using these BCG and M. intracellulare strains, we observed intracellular accumulation of ethidium bromide (EtBr). Results: We found positive correlations between Pks12 and drug resistance for all of the antibiotics tested. The drug susceptible M. intracellulare strain showed higher EtBr accumulation. Consistent with this, EtBr was much more accumulated in pks12-disrupted BCG than wild-type or the complemented strains. Conclusions: Collectively, these results suggest that Pks12 controls the multidrug resistance in part through intracellular drug accumulation.