Hf. Chambers et al., CAN PENICILLINS AND OTHER BETA-LACTAM ANTIBIOTICS BE USED TO TREAT TUBERCULOSIS, Antimicrobial agents and chemotherapy, 39(12), 1995, pp. 2620-2624
An increase in the number of tuberculosis cases caused by multiple-dru
g-resistant strains of Mycobacterium tuberculosis has stimulated searc
h for new antituberculous agents, Beta-lactam antibiotics, traditional
ly regarded as ineffective against tuberculosis, merit consideration,
Four major penicillin-binding proteins (PBPs) with approximate molecul
ar sizes of 94, 82, 52, and 37 kDa were detected by fluorography of [H
-3]penicillin-radiolabeled membrane proteins prepared from M. tubercul
osis H37Ra. The presence of membrane-associated beta-lactamase preclud
ed the use of membranes for assaying the binding affinities of beta-la
ctam antibiotics, Therefore, ampicillin affinity chromatography was us
ed to purify these four PBPs from crude membranes in order to assay th
e binding affinities of beta-lactam antibiotics, Ampicillin, amoxicill
in, and imipenem, betalactam antibiotics previously reported to be act
ive in vitro against M. tuberculosis, bound to M. tuberculosis PBPs at
therapeutically achievable concentrations, Binding of the 94-, 82-, a
nd 52-kDa PBPs, but not the 37-kDa PBP, was associated with antibacter
ial activity, suggesting that these PBPs are the critical targets, Stu
dies of mycobacterial cell wall permeability, which was assayed with a
panel of reference cephalosporins and penicillins with different char
ge positivities, indicated that the rate of penetration of beta-lactam
antibiotics to the target PBPs could not account for resistance, Resi
stance could be reversed with the beta-lactamase inhibitors clavulanat
e 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-lactamase antibiotics, These fin
dings confirm in vitro data that M. tuberculosis is susceptible to som
e beta-lactam antibiotics, Further evaluation of these drugs for the t
reatment of tuberculosis in animal models and in clinical trials is wa
rranted.