Antibacterial medicinal chemistry - what can we design for?

The need for new antibacterial agents continues to grow, but success in development of antibiotics in recent years has been limited. To improve the chances that new compounds will progress into clinical trials and beyond, it is vital that we consider as early as possible in the process the various challenges that discoverers and developers of new antibiotics will face. The author looks at the factors that affect medicinal chemistry aimed at providing successful antibacterial agents. Target selection, target inhibition, accumulation in bacteria, and pharmacokinetics are all discussed, with a particular emphasis on how our current understanding should impact design and optimization strategies. From the perspective of a medicinal chemist, the primary question when considering the various aspects of antibacterial drug discovery should be 'what can I design for?' It is important to be aware of the limitations of our understanding, and also the constraints and challenges that arise due to the diversity of the bacteria we try to address. Progress is needed to simplify approval pathways and to increase return on investment for the next generations of clinically useful agents to succeed.