The Anthelmintic Drug Niclosamide Synergizes with Colistin and Reverses Colistin Resistance in Gram-Negative Bacilli

Abstract

There is an urgent need for new therapies to overcome antimicrobial resistance especially in Gram-negative bacilli (GNB). Repurposing old U.S. Food and Drug Administration-approved drugs as complementary agents to existing antibiotics in a synergistic combination presents an attractive strategy. Here, we demonstrate that the anthelmintic drug niclosamide selectively synergized with the lipopeptide antibiotic colistin against colistin-susceptible but more importantly against colistin-resistant GNB, including clinical isolates that harbor the mcr-1 gene. Breakpoints for colistin susceptibility in resistant Gram-negative bacilli were reached in the presence of 1 g/ml (3 M) niclosamide. Reversal of colistin resistance was also observed in combinations of niclosamide and polymyxin B. Enhanced bacterial killing was evident for the combination, in comparison to colistin monotherapy, against resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. Accumulating evidence in the literature, along with our results, strongly suggests the potential for the combination of niclosamide and colistin to treat colistin-resistant Gram-negative bacillary infections. Our finding is significant since colistin is an antibiotic of last resort for multidrugresistant Gram-negative bacterial infections that are nonresponsive to conventional treatments. With the recent global dissemination of plasmid-encoded colistin resistance, the addition of niclosamide to colistin therapy may hold the key to overcome colistin resistance.

Mechanistic Understanding Enables the Rational Design of Salicylanilide Combination Therapies for Gram-Negative Infections

“…It was next reasoned that increased niclosamide influx via outer membrane permeabilization might mitigate TolC-mediated efflux. Therefore, membrane permeabilizing polymyxin antibiotics were investigated for synergy and, consistent with recent reports ( 30 – 32 ), synergy was observed when colistin or polymyxin B was coadministered with niclosamide (δ = 28.1 or 25.6, respectively) ( Fig. 3b and c ).…”

“…In isolation, niclosamide exhibits no activity against most Gram-negative pathogens ( 1 , 23 ). Nevertheless, it was recently reported that in vitro coadministration of niclosamide and colistin can overcome colistin resistance in Gram-negative bacteria ( 30 – 32 ). While these findings suggest that niclosamide may hold cryptic antibiotic potential, the molecular basis that underlies its antibiotic mode of action and synergy and the lack of efficacy against Gram-negative bacteria has been hitherto unknown.…”

Synergistic activity of colistin combined with PFK-158 against colistin-resistant and colistin-susceptible Gram-negative bacteria

“…A large quantity of previous studies have reported the synergistic activity of colistin combined with other antibiotics against colistin-resistant or carbapenem-resistant strains [18,19,20]. Besides, a few studies based on colistin in combination with the nonantibiotics were also performed previously [21,22,23]. In this study, we evaluated the synergistic activity of colistin combined with PFK-158 against colistin-resistant and colistin-susceptible Gram-negative bacteria.…”

Recent progress on elucidating the molecular mechanism of plasmid-mediated colistin resistance and drug design

“…Alternatively, natural products acting as adjuvants can be used, some of which can interact with lipopolysaccharides to perturb the outer bacterial membrane, such as pentamidine (Stokes et al 2017) and meridianin D analogs (Huggins et al 2018). In contrast, other adjuvants do not have specific roles insofar as we know, such as resveratrol (Cannatelli et al 2018), pterostilbene (Zhou et al 2018), osthole (Zhou et al 2019), and niclosamide (Domalaon et al 2019). The last but most important direction is to identify specific drugs targeting MCR.…”