Broad-spectrum therapeutics: A new antimicrobial class

Abstract

There are currently no emergency treatments for pandemics, yet drug repositioning has emerged as the foremost treatment development strategy for COVID-19, with an aim to identify successful antiviral therapeutics from safe, non-antiviral candidates. These therapeutics include antibiotics such as azithromycin and the antiparasitic nitazoxanide, both of which exhibit antiviral activity. Broad-spectrum therapeutics (BSTs) are a class of antimicrobials active against multiple pathogen types. Establishment of a developmental framework for BSTs will markedly improve global preparedness for future health emergencies.

Keywords: Antimicrobial; Broad-spectrum therapeutic; COVID-19; Drug repositioning.

Graphical abstract

Fig. 1

Repositioning history of nitazoxanide.

Fig. 2

Stages of broad-spectrum therapeutic (BST) development. Key parameters with which to evaluate emergency repositioned therapeutic candidates for pandemics are: A) Repositioning history. Candidates targeted for clinical studies can be prioritised according to their repositioning history and evidence (DREL); a longer history positively correlates with a safer and more widely used therapeutic and a large body of repositioning evidence is indicative of a broad-spectrum pharmacology (e.g. ivermectin and niclosamide). If an evaluation of a candidate's repositioning history reveals that it is DREL 4 for two or more antimicrobial classes, the candidate may directly enter PMS as a BST. B) Pharmacology. Evaluation of host-directed and pathogen-directed antimicrobial properties for both lead candidate and related compounds e.g. antiviral lysosomotropic properties of azithromycin and the wider macrolide class. C) Toxicological assessment, including the potential for antimicrobial resistance (AMR). Both pharmacological and toxicological information can be obtained from pre-existing in silico, in vitro, and preclinical studies of both the lead candidate and chemically similar compounds. D) Financial appraisal. Emergency therapeutics must be affordable by national healthcare systems in developing countries. E) Availability. Emergency therapeutics must be globally distributed to ensure sufficient deployment during a pandemic. Certain national legislations may impede obtaining a patent for further medical uses and can hinder candidate availability in certain regions. An ideal candidate would be included in the World Health Organization's List of Essential Medicines and available in all national healthcare systems. Both affordability and global availability may change after BST characterisation during post-marketing surveillance (PMS) and should be continually monitored. Overall, in addition to reduced cost and resources, drug repositioning usually takes 10–12 years compared to 15–20 for de novo drug development, which requires additional compound screening, preclinical studies, and phase I clinical trials. Successful deployment of BSTs for pandemics or bioterrorist attacks can iteratively refine and identify new use cases.