Abstract:
:An increase in the number of tuberculosis cases caused by multiple-drug-resistant strains of Mycobacterium tuberculosis has stimulated search for new antituberculous agents. Beta-lactam antibiotics, traditionally regarded as ineffective against tuberculosis, merit consideration. Four major penicillin-binding proteins (PBPs) with approximate molecular sizes of 94, 82, 52, and 37 kDa were detected by fluorography of [3H]penicillin-radiolabeled membrane proteins prepared from M. tuberculosis H37Ra. The presence of membrane-associated beta-lactamase precluded the use of membranes for assaying the binding affinities of beta-lactam antibiotics. Therefore, ampicillin affinity chromatography was used to purify these four PBPs from crude membranes in order to assay the binding affinities of beta-lactam antibiotics. Ampicillin, amoxicillin, and imipenem, beta-lactam antibiotics previously reported to be active in vitro against M. tuberculosis, bound to M. tuberculosis PBPs at therapeutically achievable concentrations. Binding of the 94-, 82-, and 52-kDa PBPs, but not the 37-kDa PBP, was associated with antibacterial activity, suggesting that these PBPs are the critical targets. Studies of mycobacterial cell wall permeability, which was assayed with a panel of reference cephalosporins and penicillins with different charge positivities, indicated that the rate of penetration of beta-lactam antibiotics to the target PBPs could not account for resistance. Resistance could be reversed with the beta-lactamase inhibitors clavulanate or sulbactam or could be circumvented by the use of a beta-lactamase-stable drug, imipenem, indicating that mycobacterial beta-lactamase, probably in conjunction with slow penetration, is a major determinant of M. tuberculosis resistance to beta-lactam antibiotics. These findings confirm in vitro data that M. tuberculosis is susceptible to some beta-lactam antibiotics. Further evaluation of these drugs for the treatment of tuberculosis in animal models and in clinical trials is warranted.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Chambers HF,Moreau D,Yajko D,Miick C,Wagner C,Hackbarth C,Kocagöz S,Rosenberg E,Hadley WK,Nikaido Hdoi
10.1128/aac.39.12.2620subject
Has Abstractpub_date
1995-12-01 00:00:00pages
2620-4issue
12eissn
0066-4804issn
1098-6596journal_volume
39pub_type
杂志文章abstract::Disk susceptibility tests with two structurally related aminoglycosides (amikacin and Sch 21420) were evaluated. Tests with 10- and 30-micrograms amikacin disks confirmed previous recommendations for interpretive zone standards; 30-micrograms disks are preferred. Tests with 10-, 20-, and 30-micrograms Sch 21420 disks ...
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journal_title:Antimicrobial agents and chemotherapy
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pub_type: 临床试验,杂志文章,随机对照试验
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