title: Can penicillins and other beta-lactam antibiotics be used to treat tuberculosis?
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.
authors.affiliation: Department of Medicine, University of California, San Francisco 94143, USA.
authors.forename: H F
authors.initials: HF
authors.lastname: Chambers
authors.forename: D
authors.initials: D
authors.lastname: Moreau
authors.forename: D
authors.initials: D
authors.lastname: Yajko
authors.forename: C
authors.initials: C
authors.lastname: Miick
authors.forename: C
authors.initials: C
authors.lastname: Wagner
authors.forename: C
authors.initials: C
authors.lastname: Hackbarth
authors.forename: S
authors.initials: S
authors.lastname: Kocagöz
authors.forename: E
authors.initials: E
authors.lastname: Rosenberg
authors.forename: W K
authors.initials: WK
authors.lastname: Hadley
authors.forename: H
authors.initials: H
authors.lastname: Nikaido
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002473:Cell Wall / Q000378:metabolism; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D006207:Half-Life; D006602:Hexosyltransferases; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008970:Molecular Weight; D002267:Muramoylpentapeptide Carboxypeptidase / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D046915:Penicillin-Binding Proteins; D010406:Penicillins / Q000378:metabolism / Q000494:pharmacology*; D010458:Peptidyl Transferases; D011485:Protein Binding; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D010406:Penicillins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase