Perspective on Antibacterial Lead Identification Challenges and the Role of Hypothesis-Driven Strategies

For the past three decades, the pharmaceutical industry has undertaken many diverse approaches to discover novel antibiotics, with limited success. We have witnessed and personally experienced many mistakes, hurdles, and dead ends that have derailed projects and discouraged scientists and business leaders. Of the many factors that affect the outcomes of screening campaigns, a lack of understanding of the properties that drive efflux and permeability requirements across species has been a major barrier for advancing hits to leads. Hits that possess bacterial spectrum have seldom also possessed druglike properties required for developability and safety. Persistence in solving these two key barriers is necessary for the reinvestment into discovering antibacterial agents. This perspective narrates our experience in antibacterial discovery—our lessons learned about antibacterial challenges as well as best practices for screening strategies. One of the tenets that guides us is that drug discovery is a hypothesis-driven science. Application of this principle, at all steps in the antibacterial discovery process, should improve decision making and possibly the odds of what has become, in recent decades, an increasingly challenging endeavor with dwindling success rates.