We report here a dehydropeptidase-deficient murine model of tuberculosis (TB) infection that is able to partially uncover the efficacy of marketed broad-spectrum beta-lactam antibiotics alone and in combination. Reductions of up to 2 log CFU in the lungs of TB-infected mice after 8 days of treatment compared to untreated controls were obtained at blood drug concentrations and time above the MIC (T->MIC) below clinically achievable levels in humans. These findings provide evidence supporting the potential of beta-lactams as safe and mycobactericidal components of new combination regimens against TB with or without resistance to currently used drugs.