Drug repurposing screens and synergistic drug-combinations for infectious diseases

Abstract

Infectious diseases account for nearly one fifth of the worldwide death toll every year. The continuous increase of drug-resistant pathogens is a big challenge for treatment of infectious diseases. In addition, outbreaks of infections and new pathogens are potential threats to public health. Lack of effective treatments for drug-resistant bacteria and recent outbreaks of Ebola and Zika viral infections have become a global public health concern. The number of newly approved antibiotics has decreased significantly in the last two decades compared with previous decades. In parallel with this, is an increase in the number of drug-resistant bacteria. For these threats and challenges to be countered, new strategies and technology platforms are critically needed. Drug repurposing has emerged as an alternative approach for rapid identification of effective therapeutics to treat the infectious diseases. For treatment of severe infections, synergistic drug combinations using approved drugs identified from drug repurposing screens is a useful option which may overcome the problem of weak activity of individual drugs. Collaborative efforts including government, academic researchers and private drug industry can facilitate the translational research to produce more effective new therapeutic agents such as narrow spectrum antibiotics against drug-resistant bacteria for these global challenges.

Linked articles: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

Figure 1

The decline of new antibiotics and rise of drug‐resistant bacteria. (A) The number of US FDA‐approved new antibiotics fell from 16 between 1983 and 1987 to 2 between 2008 and 2012. In 2012, the Generating Antibiotic Incentives (Durand et al., 2016) was signed into law, which may have contributed to the increase of approved antibiotics between 2013 and 2016. The period *2013–2016 covers 4 years. Total new molecular entities (NMEs) are above 100 during every 5‐year span between 1983 and 2016. (B) Increase of drug‐resistant Salmonella typhi, Campylobacter coli and E. coli O157 from 1999 to 2014 in the US. Data are from Centers for Disease Control and Prevention in the United States.

Figure 2

Number of FDA‐approved drugs with anti‐infective activities. (A) 310 low MW drugs that have anti‐infective activities. These compounds were curated from a total of 1578 US FDA‐approved drugs by December 2016. (B) Anti‐infective activities include antibacterial (antibiotics), antifungal, antiviral, anti‐parasitic and other anti‐infective (anthelmintic and antiprotozoal) agents. The anti‐infective activities were curated from drug@fda, http://www.accessdata.fda.gov/, MeSH, Pubmed, NCATS Pharmaceutical Collection: https://tripod.nih.gov/npc/ and https://pubchem.ncbi.nlm.nih.gov/ (Huang et al., 2011; Santos et al., 2017). Note that a drug with multiple indications is counted as one unique low MW drug.

Figure 3

Multiple indications of the rheumatoid arthritis drug, auranofin and the corresponding mechanisms of action. Auranofin was approved by US FDA for the treatment of rheumatoid arthritis. Auranofin was shown to be active in in vitro and/or preclinical models of HIV/AIDS, parasitic diseases, bacterial infections, Alzheimer's disease, Parkinson's diseases and cancer.

Figure 4

Ebola virus life cycle, host targets and repurposed drug candidates. Selected drugs are shown as an example of targeting host–pathogen system interactions to block Ebola virus infection. Note: ASM, acid sphingomyelinase; GP, glycoprotein; NPC1, niemann‐Pick C1; TPC, two‐pore channel.