Antibacterial medicinal chemistry – what can we design for?

ABSTRACT

Introduction

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.

Areas covered

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.

Expert opinion

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.

KEYWORDS:

• Antibiotics
• design strategy
• medicinal chemistry

Article highlights

• Antibacterial drug discovery is under-valued by society as a whole, and consequently is under-resourced in the pharmaceutical industry.

• Expertise is being lost, and it is vital that we continue to share knowledge and experience to maintain a functioning research base.

• Design and optimization of new small-molecule antibiotics continue to pose a very significant challenge in drug discovery.

• Killing bacteria is easy, but doing so safely in humans while minimizing propensity for resistance development requires careful target selection or a good deal of luck.

• We are beginning to understand the factors that control accumulation of molecules within bacteria, but these will likely be species-specific and so generalized rules may not be achievable.

• The difficulty in designing for a PK profile to match particular infections may mean that optimizing for unbound plasma concentration is the most sensible approach during lead optimization in the majority of cases.

This box summarizes key points contained in the article.

Acknowledgment

The author wishes to thank David Corbett and Angelo Sanzone for reading the manuscript and for helpful comments.

Declaration of interest

A Parkes is an employee of Evotec (UK) Ltd, and acts as an Expert for the GARDP-REVIVE initiative. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was supported by Evotec (UK) Ltd.