Towards the sustainable discovery and development of new antibiotics

Abstract

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

Keywords: Business strategy in drug development; Drug therapy.

Fig. 1. General scheme of antimicrobial drug development.

Large funding gaps can be seen in the early stages of hit discovery, as well as during hit and lead optimization, which are associated mainly with academic research and small and medium-sized enterprises (SMEs). Indicated figures are representative numbers of typical broad-spectrum antibiotic development programmes leading from several thousands of initial hits to the approval of at least one marketable candidate^,–. *Timings are dependent on a number of factors and can vary greatly. A minimum to maximum range for complete development (discovery to market) is 8–18 years (average 13–14 years). **The cost per molecule/candidate (in million euros, m€) does not include extended costs for attrition (failed programmes) and lost opportunities associated with increased cycle time until reaching the next development phase; such extensions can increase the required budget for the early stages up to 50–100 m€ (refs^,,). N (orange diamond), nomination of (pre)clinical candidate(s); PPPs, public–private partnerships; ROI, return on investment.

Fig. 2. Summary of major steps and processes in antibacterial drug discovery and development.

Approaches marked with * can be linked with emerging artificial intelligence (AI)-based technology, for example, for advanced data mining, screening or property predictions, to increase efficiency and outcome. ADMET, absorption, distribution, metabolism, excretion and toxicity; CTA, clinical trial application; DRF, dose range finding; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; FoR, frequency of resistance; GLP, good laboratory practice; ICH, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; IND, investigational new drug; MedChem, medicinal chemistry; MICs, minimal inhibitory concentrations; MoR, mechanism of resistance; phys-chem, physicochemical properties; PK/PD, pharmacokinetics/pharmacodynamics; POC, proof of concept; SAR, structure–activity relationship; TPP, target product profile.