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Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 β-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill

Diazetidinones were first prepared over 100 years ago via ketene plus azo-compound cycloaddition. Subsequent studies have provided multiple successful synthetic strategies utilizing intramolecular ring cyclization chemistry as well as ring contraction reactions. While much of the early work in this arena produced diazetidinones heavily substituted with aryl substituents, more recent effort has turned to the preparation and study of simpler and specifically designed analogs including the parent 1,2-diazetidin-3-one itself. Significant effort has gone into trying to prepare aza-β-lactam analogs of the β-lactam antibiotics, a logical extension of the chemistry. Unfortunately, this objective has eluded the best efforts of several investigators due to the unique chemical properties and reactivity of these novel heterocycles. The diversity of substitutions now readily available on the diazetidinone core has inspired others to incorporate this unique ring into other chemotypes, and an increasing number of biologically active molecules that contain a diazetidinone ring are now being reported.

The use of ketone 2,4,6-triisopropylbenzenesulfonylhydrazones to generate alkenylcuprate reagents that add in 1,4-fashion to enones is described.