A series of benzothiazinones (BTZs) containing an oxime moiety, based on the structure of ZR-10 discovered in our lab, were designed and synthesized. Most of the compounds with alkoxyimino groups attached to the piperazine or cyclohexyl ring of PBTZ169, exhibit excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016-0.037 μg/mL) and low cell cytotoxicity. Two close PBTZ169-analogues 3a and 3b with proper ADME/T and PK properties show potent in vivo efficacy in an acute mouse model of tuberculosis. Compound 3a is under evaluation as a potential clinical candidate for treatment of tuberculosis.