Abstract
Treatment of infections caused by Mycobacterium avium complex bacteria still remains a challenge since these organisms are resistant to a majority of antituberculous drugs. M. avium is very often linked with acquired immune deficiency syndrome-associated opportunistic infections. We earlier suggested that one of the strategies for circumventing multiple-drug resistance might be the enhancement of M. avium drug susceptibility by inhibiting the synthesis of the outermost layer of its envelope, which appears to act as an exclusionary barrier for drugs. In this investigation, we have examined this strategy by simultaneously using drugs and the following inhibitors of the M. avium cell envelope: m-fluoro-phenylalanine (an inhibitor of mycoside-C biosynthesis), DL-norleucine (an inhibitor of transmethylation reactions), ethambutol (an inhibitor of arabinogalactan synthesis), EDTA (a divalent-ion chelator), and colistin (an inducer of membrane flux of divalent cations). All the drugs were used in concentrations which were low enough for a possible medical application to be foreseen. This approach, tested on seven strains of the M. avium complex, showed that both m-fluoro-phenylalanine and ethambutol were interesting candidates because they caused significant enhancement of M. avium drug susceptibility.
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Selected References
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- David H. L. Basis for lack of drug susceptibility of atypical mycobacteria. Rev Infect Dis. 1981 Sep-Oct;3(5):878–884. doi: 10.1093/clinids/3.5.878. [DOI] [PubMed] [Google Scholar]
- David H. L., Clavel-Seres S., Clement F., Goh K. S. Uptake of selected antibacterial agents in Mycobacterium avium. Zentralbl Bakteriol Mikrobiol Hyg A. 1987 Jul;265(3-4):385–392. [PubMed] [Google Scholar]
- David H. L., Clavel-Seres S., Clément F., Lazlo A., Rastogi N. Methionine as methyl-group donor in the synthesis of Mycobacterium avium envelope lipids, and its inhibition by DL-ethionine, D-norleucine and DL-norleucine. Acta Leprol. 1989;7 (Suppl 1):77–80. [PubMed] [Google Scholar]
- David H. L., Rastogi N. Antibacterial action of colistin (polymyxin E) against Mycobacterium aurum. Antimicrob Agents Chemother. 1985 May;27(5):701–707. doi: 10.1128/aac.27.5.701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- David H. L., Rastogi N., Clavel-Sérès S., Clément F., Thorel M. F. Structure of the cell envelope of Mycobacterium avium. Zentralbl Bakteriol Mikrobiol Hyg A. 1987 Apr;264(1-2):49–66. doi: 10.1016/s0176-6724(87)80124-4. [DOI] [PubMed] [Google Scholar]
- Etzkorn E. T., Aldarondo S., McAllister C. K., Matthews J., Ognibene A. J. Medical therapy of Mycobacterium avium-intracellulare pulmonary disease. Am Rev Respir Dis. 1986 Sep;134(3):442–445. doi: 10.1164/arrd.1986.134.3.442. [DOI] [PubMed] [Google Scholar]
- Heifets L. B., Iseman M. D., Lindholm-Levy P. J. Ethambutol MICs and MBCs for Mycobacterium avium complex and Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1986 Dec;30(6):927–932. doi: 10.1128/aac.30.6.927. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoffner S. E., Källenius G., Beezer A. E., Svenson S. B. Studies on the mechanisms of the synergistic effects of ethambutol and other antibacterial drugs on Mycobacterium avium complex. Acta Leprol. 1989;7 (Suppl 1):195–199. [PubMed] [Google Scholar]
- Hoffner S. E., Svenson S. B., Källenius G. Synergistic effects of antimycobacterial drug combinations on Mycobacterium avium complex determined radiometrically in liquid medium. Eur J Clin Microbiol. 1987 Oct;6(5):530–535. doi: 10.1007/BF02014241. [DOI] [PubMed] [Google Scholar]
- Kilburn J. O., Takayama K. Effects of ethambutol on accumulation and secretion of trehalose mycolates and free mycolic acid in Mycobacterium smegmatis. Antimicrob Agents Chemother. 1981 Sep;20(3):401–404. doi: 10.1128/aac.20.3.401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rastogi N., David H. L. Ultrastructural and chemical studies on wall-deficient forms, spheroplasts and membrane vesicles from Mycobacterium aurum. J Gen Microbiol. 1981 May;124(1):71–79. doi: 10.1099/00221287-124-1-71. [DOI] [PubMed] [Google Scholar]
- Rastogi N., Frehel C., Ryter A., Ohayon H., Lesourd M., David H. L. Multiple drug resistance in Mycobacterium avium: is the wall architecture responsible for exclusion of antimicrobial agents? Antimicrob Agents Chemother. 1981 Nov;20(5):666–677. doi: 10.1128/aac.20.5.666. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rastogi N., Goh K. S., David H. L. Drug susceptibility testing in tuberculosis: a comparison of the proportion methods using Lowenstein-Jensen, Middlebrook 7H10 and 7H11 agar media and a radiometric method. Res Microbiol. 1989 Jul-Aug;140(6):405–417. doi: 10.1016/0923-2508(89)90016-8. [DOI] [PubMed] [Google Scholar]
- Rastogi N., Moreau B., Capmau M. L., Goh K. S., David H. L. Antibacterial action of amphipathic derivatives of isoniazid against the Mycobacterium avium complex. Zentralbl Bakteriol Mikrobiol Hyg A. 1988 Jun;268(4):456–462. doi: 10.1016/s0176-6724(88)80123-8. [DOI] [PubMed] [Google Scholar]
- Rastogi N., Potar M. C., Henrotte J. G., Franck G., David H. L. Further studies on colistin (polymyxin E)-induced cell leakage in mycobacteria: Mg++ efflux in Mycobacterium avium and its effects on drug-susceptibility. Zentralbl Bakteriol Mikrobiol Hyg A. 1988 Apr;268(2):251–258. doi: 10.1016/s0176-6724(88)80010-5. [DOI] [PubMed] [Google Scholar]
- Reading C., Cole M. Clavulanic acid: a beta-lactamase-inhiting beta-lactam from Streptomyces clavuligerus. Antimicrob Agents Chemother. 1977 May;11(5):852–857. doi: 10.1128/aac.11.5.852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Soper T. S., Manning J. M. Synergy in the antimicrobial action of penicillin and beta-chloro-D-alanine in vitro. Antimicrob Agents Chemother. 1976 Feb;9(2):347–349. doi: 10.1128/aac.9.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takayama K., Armstrong E. L., Kunugi K. A., Kilburn J. O. Inhibition by ethambutol of mycolic acid transfer into the cell wall of Mycobacterium smegmatis. Antimicrob Agents Chemother. 1979 Aug;16(2):240–242. doi: 10.1128/aac.16.2.240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takayama K., Kilburn J. O. Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis. Antimicrob Agents Chemother. 1989 Sep;33(9):1493–1499. doi: 10.1128/aac.33.9.1493. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takayama K., Wang L., David H. L. Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1972 Jul;2(1):29–35. doi: 10.1128/aac.2.1.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Winder F. G., Collins P. B. Inhibition by isoniazid of synthesis of mycolic acids in Mycobacterium tuberculosis. J Gen Microbiol. 1970 Sep;63(1):41–48. doi: 10.1099/00221287-63-1-41. [DOI] [PubMed] [Google Scholar]
- Woodley C. L., David H. L. Effect of temperature on the rate of the transparent to opaque colony type transition in Mycobacterium avium. Antimicrob Agents Chemother. 1976 Jan;9(1):113–119. doi: 10.1128/aac.9.1.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Young L. S., Inderlied C. B., Berlin O. G., Gottlieb M. S. Mycobacterial infections in AIDS patients, with an emphasis on the Mycobacterium avium complex. Rev Infect Dis. 1986 Nov-Dec;8(6):1024–1033. doi: 10.1093/clinids/8.6.1024. [DOI] [PubMed] [Google Scholar]