5-Methylindole Potentiates Aminoglycoside Against Gram-Positive Bacteria Including Staphylococcus aureus Persisters Under Hypoionic Conditions

Abstract

Antibiotic resistance/tolerance has become a severe threat to human and animal health. To combat antibiotic-resistant/tolerant bacteria, it is of significance to improve the efficacy of traditional antibiotics. Here we show that indole potentiates tobramycin to kill stationary-phase Staphylococcus aureus cells after a short, combined treatment, with its derivative 5-methylindole being the most potent compound tested and with the absence of ions as a prerequisite. Consistently, this combined treatment also kills various types of S. aureus persister cells as induced by the protonophore CCCP, nutrient shift, or starvation, as well as methicillin-resistant S. aureus (MRSA) cells. Importantly, 5-methylindole potentiates tobramycin killing of S. aureus persisters in a mouse acute skin wound model. Furthermore, 5-methylindole facilitates killing of many strains of gram-positive pathogens such as Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes by aminoglycoside antibiotics, whereas it suppresses the action of aminoglycoside against the gram-negative pathogens Escherichia coli and Shigella flexneri. In conclusion, our work may pave the way for the development of indole derivatives as adjuvants to potentiate aminoglycosides against gram-positive pathogens.

Combatting Persister Cells With Substituted Indoles

“…Although there is one report claiming indole increases persistence with E. coli (Vega et al, 2012), consistent and overwhelming evidence has shown indole and substituted indoles reduce persistence in both Bacteria and Archaea (Hu et al, 2015;Kwan et al, 2015;Lee et al, 2016;Megaw and Gilmore, 2017;Li et al, 2019;Song et al, 2019;Manoharan et al, 2020;Masuda et al, 2020;Sun et al, 2020;Yam et al, 2020). For years, this was perplexing but it seems the most-probable reason for this different result lies in the solvent utilized to solubilize indole.…”

“…Indole derivatives have also been combined both with antibiotics and metals to increase their effectiveness in persister cell killing. For example, 5-methylindole (Figure 3) combined with tobramycin kills methicillin-resistant S. aureus and Staphylococcus epidermidis persisters (Sun et al, 2020). In addition, 5-nitroindole (Figure 3) kills E. coli, P. aeruginosa, and Enterobacter tabaci persister cells, and its effectiveness was increased by combining it with copper and zinc nanoparticles (Manoharan et al, 2020).…”

Gentamicin Combined With Hypoionic Shock Rapidly Eradicates Aquaculture Bacteria in vitro and in vivo

“…For example, Peng et al (2015) found that exogenous glucose or alanine plus kanamycin can kill multidrug-resistant Edwardsiella tarda both in vitro and in a mouse model for urinary tract infection. Glycerol monolaurate, lauric acid, 5-methylindole, and even the commonly used diabetic drug metformin were found to act synergistically with aminoglycoside to eliminate Staphylococcus aureus persisters ( Hess et al, 2014 ; Liu et al, 2020 ; Sun et al, 2020 ). Various adjuvants, including metabolites ( Allison et al, 2011 ; Peng et al, 2015 ), for antibiotic potentiation have been well documented ( Liu et al, 2019 ).…”

Are we really studying persister cells?

“…However, robust techniques exist for creating bona fide persister cells including stopping translation (Kwan et al ., 2013), production of toxins (Hong et al ., 2012; Chowdhury et al ., 2016), and pretreatment with non‐lethal stress such as acid and hydrogen peroxide (Hong et al ., 2012). For example, the pretreatment method of stopping transcription to cease translation to create persister cells has been vetted eight ways (Kim et al ., 2018b) and this approach has been used by 11 groups to date to study persistence (Kwan et al ., 2013; Grassi et al ., 2017; Cui et al ., 2018; Narayanaswamy et al ., 2018; Sulaiman et al ., 2018; Tkhilaishvili et al ., 2018; Pu et al ., 2019; Rowe et al ., 2020; Sun et al ., 2020; Yu et al ., 2020; Zhao et al ., 2020).…”