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.
The profiles of the interaction of antimycobacterial drugs with macrophage (MPhi) 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 H(2)O(2)-halogen (H(2)O(2)-Fe(2+)-NaI)-mediated bactericidal system, reactive nitrogen intermediates (RNIs), and free fatty acids (FFAs), which are known as central antimicrobial effectors of host MPhis 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 H(2)O(2)-Fe(2+)-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 H(2)O(2)-Fe(2+)-NaI system. This phenomenon is specific to the H(2)O(2)-Fe(2+)-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 MPhis against intracellular MAC organisms.
Sano
Keisuke
K
Department of Microbiology and Immunology, Shimane University School of Medicine, Izumo, Shimane 693-8501, Japan.
Tomioka
Haruaki
H
Sato
Katsumasa
K
Sano
Chiaki
C
Kawauchi
Hideyuki
H
Cai
Shanshan
S
Shimizu
Toshiaki
T
D000890:Anti-Infective Agents / Q000494:pharmacology*; D015169:Colony Count, Microbial; D005230:Fatty Acids, Nonesterified / Q000096:biosynthesis / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D015269:Mycobacterium avium Complex / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012974:Sodium Iodide / Q000494:pharmacology
D000890:Anti-Infective Agents; D005230:Fatty Acids, Nonesterified; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D007501:Iron; D009195:Peroxidase; D012974:Sodium Iodide