Abstract
Members of the Mycobacterium avium complex are the most frequently encountered opportunistic bacterial pathogens among patients in the advanced stage of AIDS. Two clinical isolates of the same strain, numbers 397 and 417, were obtained from an AIDS patient with disseminated M. avium complex infection before and after treatment with a regimen of clarithromycin and ethambutol. To identify the biochemical consequence of drug treatment, the expression and chemical composition of their major cell wall constituents, the arabinogalactan, lipoarabinomannan, and the surface glycopeptidolipids (GPL), were critically examined. Through thin layer chromatography, mass spectrometry, and chemical analysis, it was found that the GPL expression profiles differ significantly in that several apolar GPLs were overexpressed in the clinically resistant 417 isolate at the expense of the serotype 1 polar GPL, which was the single predominant band in the ethambutol-susceptible 397 isolate. Thus, instead of additional rhamnosylation on the 6-deoxytalose (6-dTal) appendage to give the serotype 1-specific disaccharide hapten, the accumulation of this nonextended apolar GPL probably provided more precursor substrate available for further nonsaccharide substitutions including a higher degree of O-methylation to give 3-O-Me-6-dTal and the unusual 4-O-sulfation on 6-dTal. Further data showed that this alteration effectively neutralized ethambutol, which is known to inhibit arabinan synthesis. Thus, in contrast with derived Emb-resistant mutants of Mycobacterium smegmatis or Mycobacterium tuberculosis, which are devoid of a surface GPL layer, the lipoarabinomannan from resistant 417 isolate grown in the presence of this drug was not apparently truncated.
Highlights
From the §Department of Microbiology, Colorado State University, Fort Collins, Colorado 80523 and the Members of the Mycobacterium avium complex are the most frequently encountered opportunistic bacterial pathogens among patients in the advanced stage of AIDS
Clinical isolates 397 and 417 of Mycobacterium avium complex (MAC) from an AIDS patient with disseminated MAC infection were determined to be the same strain by comparing large restriction fragments of genomic DNA separated by pulsed field gel electrophoresis
2151, serotype 2) that was originally isolated from a sputum sample of a patient with pulmonary MAC infection were analyzed in parallel
Summary
(Received for publication, December 2, 1998, and in revised form, January 15, 1999). Kay-Hooi Khoo‡, Elke Jarboe§, Adam Barker§, Jordi Torrelles§, Chu-Wei Kuo‡, and Delphi Chatterjee§¶. Two clinical isolates of the same strain, numbers and 417, were obtained from an AIDS patient with disseminated M. avium complex infection before and after treatment with a regimen of clarithromycin and ethambutol. To identify the biochemical consequence of drug treatment, the expression and chemical composition of their major cell wall constituents, the arabinogalactan, lipoarabinomannan, and the surface glycopeptidolipids (GPL), were critically examined. Two clinical isolates of the same strains from an AIDS patient with disseminated MAC infection before and after treatment with a regimen of clarithromycin and Emb were investigated. By definition, these are virulent strains, and the post-treatment isolate is naturally and clinically drug-resistant. The dose-dependent action of Emb on arabinan synthesis [9, 10] was neutralized with no apparent effect on LAM
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