Curcumin alleviates persistence of Acinetobacter baumannii against colistin

Abstract

Persisters are phenotypic variants of normal susceptible bacterial populations that survive prolonged exposure to high doses of antibiotics and are responsible for pertinacious infections and post-treatment relapses. Out of the three antibiotics, Acinetobacter baumannii formed the highest percentage of persister cells against rifampicin followed by amikacin and the least against colistin. Colistin-treated cells formed the high levels of reactive oxygen species (ROS) whose quenching with bipyridyl and thiourea led to an increased persister population. Curcumin, a polyphenolic pro-oxidant, significantly decreased persistence against colistin. The quenching of ROS generated by curcumin-colistin combination and the use of resveratrol, an anti-oxidant, with colistin increased the persister population, supporting the significance of ROS in decreased persistence against this combination. The down-regulation of repair genes by this combination in comparison to colistin alone supported the modulation of gene expression in response to ROS and their importance in decreased persistence. Increased membrane permeability by colistin, facilitating the penetration of curcumin into cells and resulting in increased ROS and compromised repair compounded by the decreased efflux of colistin by the inhibition of efflux pumps, may be responsible for enhanced lethality and low persistence. Hence, the curcumin-colistin combination can be another option with anti-persister potential for the control of chronic A. baumannii infections.

Rapid Killing and Biofilm Inhibition of Multidrug-Resistant Acinetobacter baumannii Strains and Other Microbes by Iodoindoles

“…ROS generation in A. baumannii was assayed as described previously [39]. Briefly, overnight grown cells of A. baumannii ATCC 17978 in TSB were harvested, washed and re-suspended at 10 6 CFU/mL in PBS.…”

“…To understand the mechanism responsible for 5-iodoindole induced cell death, we first investigated its effects on membrane integrity using colistin as a positive control, which has been reported to induce surface roughness and disrupt membrane integrity [39]. SEM analysis showed obvious cell shrinkage after treatment with 5-iodoindole at 125 µg/mL for 60 min ( Figure 5 and Figure S4).…”

Non-walled spherical Acinetobacter baumannii is an important type of persister upon β -lactam antibiotic treatment

“…In addition to the widespread of drug resistance, A. baumannii persistence also contributes to the treatment failure even at high doses of antibiotics [20]. Despite the endeavours have been made to understand the persistence and its eradication [21][22][23][24], the mechanism for persistence formation in A. baumannii is yet to be fully understood.…”

Polymyxins–Curcumin Combination Antimicrobial Therapy: Safety Implications and Efficacy for Infection Treatment

“…Curcumin, also known as diferuloylmethane, E100 or natural yellow 3 (International Union of Pure and Applied Chemistry (IUPAC) name is (1E, 6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, Figure 1 b), is a natural polyphenol extracted from the rhizome of Curcuma longa [ 39 ]. Curcumin displays many beneficial pharmacological actives, such as anti-inflammatory, anti-oxidant, antitumor and notably, antimicrobial activities [ 24 , 40 , 41 , 42 , 43 ]. The direct antibacterial activities of curcumin have been widely studied [ 44 , 45 ].…”

“…Natural products have been the source of most of our antibacterial armamentarium and efforts over the last 30 years [ 22 ]. Recent studies have shown that combining polymyxins with curcumin has many pharmacological and toxicological benefits over monotherapy with each compound per se including: (1), the in vitro synergy against various strains of MDR bacteria [ 23 ], including polymyxin resistant isolates [ 24 ]; (2), protection against polymyxin-induced nephron- and neuro-toxicity [ 25 , 26 , 27 ]; (3), curcumin supplementation improves recovery from the bacterial infection or LPS—induced inflammatory response or sepsis [ 28 , 29 , 30 , 31 , 32 , 33 ]. Importantly, human clinical trials indicated that curcumin displays good safety and tolerability [ 34 , 35 , 36 ]; oral administration of curcumin at eight grams per day over three months or a single oral dose of 12 grams has no marked adverse effect [ 37 , 38 ].…”