Antimicrobial Drug Discovery Against Persisters

Abstract

The efficacy of most currently prescribed antibiotics that target biosynthetic processes during cell growth or cellular uptake is energy dependent. However, because persisters are non-growing, dormant cell population with low-energy metabolic states (Conlon et al., Nature Microbiology, 1, 2016; Lewis, Annual Review of Microbiology, 64, 357, 2010; Shan et al., MBio, 8, 2017), conventional antibiotics fail to effectively eliminate bacterial persisters, which may lead to chronic and reoccurring infection (Lewis, Annual Review of Microbiology, 64, 357, 2010). The lack of antibiotics to treat infections caused by persisters entreats the urgency for developing new therapeutics effective against bacterial persisters. In response to this dire need, several strategies and anti-persister antimicrobials have been developed. Anti-persister strategies can be grouped into two approaches (1) direct killing of persisters through growth-independent targets and (2) converting persisters to antibiotic susceptible states by antibiotic adjuvants. In this chapter, we review growth-independent targets, such as bacterial proteases (Conlon, Nature, 503, 365–370, 2013), membrane lipid bilayers (Hurdle et al., Nature Reviews Microbiology, 9, 62–75, 2011), and bacterial DNA (Kwan et al., Environmental Microbiology, 2015). We also discuss a Caenorhabditis elegans-based screening strategy to identify membrane-active antimicrobials with relatively low cytotoxicity, which overcomes the membrane selectivity issue (Kim et al., ACS Infectious Diseases, 4, 1540–1545, 2018b, Nature, 556, 103–107, 2018c). Lastly, we review antibiotic adjuvants that resuscitate persisters to conventional antibiotic susceptible conditions (Allison et al., Nature, 473, 216–220, 2011). Included among these strategies, we explore the engineering of conventional antibiotics conjugated with drug carriers such as a peptide and an antibody that facilitate uptake or accessibility of antibiotics (Brezden et al., Journal of the American Chemical Society, 138, 10945–10949, 2016; Lehar et al., Nature, 527, 323–328, 2015; Schmidt et al., ACS Nano, 8, 8786–8793, 2014).