Tuberculosis (TB) is a highly infectious disease caused by Mycobacterium tuberculosis (Mtb), one of the most dangerous aerobic bacteria. The need for long-term treatments and the increase in drug resistance mechanisms make it necessary to urgently develop new strategies to combat this potentially lethal pathogen. beta-Lactam Antibiotics (BLA) are the most widely used and safest antibiotics in the clinic and include several classes such as penicillins, cephalosporins and carbapenems. However, historically these agents have not been used to treat TB. There are two mechanisms of resistance to BLA in Mtb: the cell envelope rich in lipoglycans which acts as a barrier for the penetration of many drugs, including BLA, and the expression of BlaC, a specific beta-lactamase enzyme capable of hydrolyze and inactivate the BLA. Recent studies have shown that the combination of meropenem (a beta-lactam carbapenem), amoxicillin (a beta-lactam penicillin) and clavulanate (a beta-Lactamase inhibitor) markedly reduced the Mtb load in the patient’s sputum after two weeks, therefore giving new hope to the use of BLA to tackle the tuberculosis epidemic. This proposal aims to develop new compounds that behave as BLA adjuvant for anti-Mtb treatment with a dual mechanism of action. We will design and synthesize novel Boronic Acid Transition State Inhibitors (BATSIs) as inhibitors of BlaC, the beta-lactamase expressed in Mtb, and investigate whether they can be derivatized to become disrupting agents of Mtb’s unique outer “capsule” made of lipoglycans, to promote better penetration of drugs into the cell. This project will also investigate the possibility of improving the penetration of molecules into the necrotic granuloma formed in vivo as part of the disease process, by developing a lipid-based prodrug strategy. To achieve these specific objectives, the project will be divided into three main work packages, involving a combination of biological, chemical, and analytical expertise.