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Antimicrobial Agents and Chemotherapy, June 2004, p. 2132-2139, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2132-2139.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Interaction of Antimycobacterial Drugs with the Anti-Mycobacterium avium Complex Effects of Antimicrobial Effectors, Reactive Oxygen Intermediates, Reactive Nitrogen Intermediates, and Free Fatty Acids Produced by Macrophages

Keisuke Sano,1,2 Haruaki Tomioka,1* Katsumasa Sato,1 Chiaki Sano,1 Hideyuki Kawauchi,2 Shanshan Cai,1 and Toshiaki Shimizu1

Department of Microbiology and Immunology,1 Department of Otorhinolaryngology, Shimane University School of Medicine, Izumo, Shimane 693-8501, Japan2

Received 23 July 2003/ Returned for modification 29 September 2003/ Accepted 23 February 2004

The profiles of the interaction of antimycobacterial drugs with macrophage (M{Phi}) antimicrobial mechanisms have yet to be elucidated in detail. We examined the effects of various antimycobacterial drugs on the anti-Mycobacterium avium complex (MAC) antimicrobial activity of reactive oxygen intermediates (ROIs), especially of an H2O2-halogen (H2O2-Fe2+-NaI)-mediated bactericidal system, reactive nitrogen intermediates (RNIs), and free fatty acids (FFAs), which are known as central antimicrobial effectors of host M{Phi}s against mycobacterial pathogens. We have found that certain drugs, such as rifampin (RIF), rifabutin (RFB), isoniazid (INH), clofazimine (CLO), and some fluoroquinolones, strongly or moderately reduced the anti-MAC activity of the H2O2-Fe2+-NaI system, primarily by inhibiting the generation of hypohalite ions and in part by interfering with the halogenation reaction of bacterial cell components due to the H2O2-Fe2+-NaI system. This phenomenon is specific to the H2O2-Fe2+-NaI system, since these drugs did not reduce the anti-MAC activity of RNIs and FFAs. From the perspective of the chemotherapy of MAC infections, the present findings indicate an important possibility that certain antimycobacterial drugs, such as rifamycins (RIF and RFB), INH, CLO, and also some types of fluoroquinolones, may interfere with the ROI-mediated antimicrobial mechanisms of host M{Phi}s against intracellular MAC organisms.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Shimane University School of Medicine, Izumo, Shimane 693-8501, Japan. Phone: 81 853 20 2146. Fax: 81 853 20 2145. E-mail: tomioka{at}med.shimane-u.ac.jp.

Antimicrobial Agents and Chemotherapy, June 2004, p. 2132-2139, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2132-2139.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.





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