Discovery and preclinical development of new antibiotics

Abstract

Antibiotics are the medical wonder of our age, but an increasing frequency of resistance among key pathogens is rendering them less effective. If this trend continues the consequences for cancer patients, organ transplant patients, and indeed the general community could be disastrous. The problem is complex, involving abuse and overuse of antibiotics (selecting for an increasing frequency of resistant bacteria), together with a lack of investment in discovery and development (resulting in an almost dry drug development pipeline). Remedial approaches to the problem should include taking measures to reduce the selective pressures for resistance development, and taking measures to incentivize renewed investment in antibiotic discovery and development. Bringing new antibiotics to the clinic is critical because this is currently the only realistic therapy that can ensure the level of infection control required for many medical procedures. Here we outline the complex process involved in taking a potential novel antibiotic from the initial discovery of a hit molecule, through lead and candidate drug development, up to its entry into phase I clinical trials. The stringent criteria that a successful drug must meet, balancing high efficacy in vivo against a broad spectrum of pathogens, with minimal liabilities against human targets, explain why even with sufficient investment this process is prone to a high failure rate. This emphasizes the need to create a well-funded antibiotic discovery and development pipeline that can sustain the continuous delivery of novel candidate drugs into clinical trials, to ensure the maintenance of the advanced medical procedures we currently take for granted.

Key words::

• Candidate drug
• efficacy
• hit molecule
• lead molecule
• liability testing
• medicinal chemistry

Declaration of interest: D.H. acknowledges support from Vetenskapsrådet (Swedish Science Council), SSF (Swedish Strategic Science Foundation), Vinnova (Swedish Innovation Science), and the Knut and Alice Wallenberg Foundation (RiboCore Project). A.K. acknowledges support from Vinnova (Swedish Innovation Science). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.