•Appreciation for bacterial physiology during infection will impact discovery.•Following CLSI guidelines can prevent accurate prediction of compound utility.•New antibacterial screening strategies may identify new drug targets/pathways.An impending disaster is currently developing in the infectious disease community: the combination of rapidly emerging multidrug-resistance among clinically relevant bacterial pathogens, together with an unprecedented withdrawal from industrial dedication to this disease area, is jeopardizing human health on a societal level. For those who remain focused and dedicated to identifying solutions to this growing problem, additional challenges await when in vitro activity does not correlate with in vivo efficacy. Thus the development of more effective translational assays will greatly improve and streamline the process of identifying novel antibacterial agents that can stand the test of preclinical and clinical development. Here we describe recent examples of research that justify the need for such assays.

•Antibiotic resistance levels have reached critically high levels.•Antibiotic discovery efforts have reached critically low levels.•Governments are attempting to incentivize reinvestment in antibiotic development.•Federal funding of antibacterial research is dwarfed by that of other disease areas.Antibiotics have been the most transformative medicines in the history of human health. Although once considered a mainstay in the pipeline of most major players in the pharmaceutical industry, new antibiotic discovery and development efforts have been minimalized as a consequence of challenges attributed to the identification of new chemical matter, the increasing complexity of stringent regulatory requirements, and the dwindling economic incentives that justify the early-stage investments. Catastrophically, this discovery void comes at a time when antibiotic resistance emergence and spread has reached unprecedented levels, fueling the clinical desperation for novel molecules that are not impacted by relevant resistance mechanisms. This review will discuss recent economic and regulatory attempts to revitalize the antibiotic discovery space.