Inhibition of the multidrug efflux pump LmrS from Staphylococcus aureus by cumin spice Cuminum cyminum

Abstract

Staphylococcus aureus is a serious causative agent of infectious disease. Multidrug-resistant strains like methicillin-resistant S. aureus compromise treatment efficacy, causing significant morbidity and mortality. Active efflux represents a major antimicrobial resistance mechanism. The proton-driven multidrug efflux pump, LmrS, actively exports structurally distinct antimicrobials. To circumvent resistance and restore clinical efficacy of antibiotics, efflux pump inhibitors are necessary, and natural edible spices like cumin are potential candidates. The mode of cumin antibacterial action and underlying mechanisms behind drug resistance inhibition, however, are unclear. We tested the hypothesis that cumin inhibits LmrS drug transport. We found that cumin inhibited bacterial growth and LmrS ethidium transport in a dosage-dependent manner. We demonstrate that cumin is antibacterial toward a multidrug-resistant host and that resistance modulation involves multidrug efflux inhibition.

Functional and Structural Roles of the Major Facilitator Superfamily Bacterial Multidrug Efflux Pumps

“…EmrB from Escherichia coli Phenylalanine arginyl β-naphthylamide (PAβN) and 1-(1-naphthyl methyl)-piperazine (NMP) [127] EmrD-3 from Vibrio cholerae Garlic, allyl sulfide [128] LmrP from Lactococcus lactis Verapamil and quinine Nicardipine and vinblastine Tetraphenyl phosphonium [129] QacA from Staphylococcus aureus Hydantoin, silybin [130,131] MdfA from Escherichia coli Reserpine [132] QacB from Staphylococcus aureus Silybin [131] LmrS from Staphylococcus aureus Cumin seed oil, cumin aldehyde, reserpine [133] NorA from Staphylococcus aureus 3-aryl piperidines [134] Berberine [135] Reserpine [136] Omeprazole, lansoprazole [137] GG918, tariquidar (primary active transport inhibitors) [138,139] Verapamil, ciprofloxacin, ofloxacin [140] 5,9 dimethyl-deca-2,4,8-trienoic acid, 9-formyl-5-methyl-deca-2,4,8-trienoic acid [141] Chlorpromazine, thioridazine, and prochlorperazine [142][143][144] Kaempferol rhamnoside [145] Chalones [146] COX Coumarin [148] Genistein (flavonoid compound) [131] Ginsenoside 20(S)-Rh2 [149] Boronic acid molecules, 6-(3-phenylpropoxy) pyridine-3-boronic acid and 6-(4-phenylbutoxy) pyridine-3-boronic acid [150] Silybin [151] 5 -methoxy-hydnocarpin, pheophorbide A, 5 -MHC, curcumin, kaempferol, silibinin, isoflavone, orizabins, capsaicin, tannic acid, [152] nerol, dimethyl octanol, estragole [153] Riparin B [154] Olaanolic acid, ulvaol [155] Brachydins: BR-A, BR-B [156] One of the earliest clear examples of modulation upon a major facilitator superfamily antimicrobial efflux pump was that of the energy uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) and the TetA(C) tetracycline efflux pump [157], demonstrating that the pump was a secondary active transporter. Since this...…”

“…Similarly, the QacA efflux pump from S. aureus represents another well-studied target for modulation by a large number of inhibitors, which have been extensively reviewed [124,164,165]. In our laboratory, we discovered that the non-toxic cumin spice extract and its bioactive agent cuminaldehyde inhibited resistance and efflux, respectively, which were mediated by the multidrug efflux pump LmrS from S. aureus [133,166]. More recently, brachydin-based compounds extracted from extracts of Arrabidaea brachypoda were shown to inhibit both the growth of S. aureus and NorA drug efflux [156].…”

Nigella sativa essential oil and its bioactive compounds as resistance modifiers against Staphylococcus aureus

“…Staphylococcus aureus is the most human pathogenic staphylococcal species and the most common cause of life‐threatening skin and soft‐tissue infection (Kakarla et al, ). In spite of the clinical availability of antimicrobials against S. aureus infections, the death rate associated with serious infection is about 20–25% because of the appearance of drug‐resistant isolates such as methicillin resistant S. aureus (MRSA; Fridkin et al, ).…”

Transcriptional Regulator TetR21 Controls the Expression of the Staphylococcus aureus LmrS Efflux Pump

“…Thus, we tested the tetR21 mutant for effects on the expression of other known efflux pump genes and found increased expression of lmrS and sdrM. Overexpression of lmrS but not sdrM from a plasmid generated resistance to chloramphenicol and other LmrS substrates previously reported (2,10), and a tetR21-lmrS double mutant eliminated the non-tetracycline resistance phenotypes found in QT21 with the exception of the low-level norfloxacin resistance. Thus, tetR21 regulates tet38 and lmrS in S. aureus and contributes to multiple low-level resistances.…”

“…Several staphylococcal efflux pumps, such as NorA, NorB, NorC, Tet38, MdeA, SepA, LmrS, and SdrM, contribute to multiple drug resistance (MDR) (2-9). LmrS, a major facilitator superfamily (MFS) efflux pump that showed homology with the lincomycin resistance efflux pump of Bacillus and Lactobacillus species, was found to confer resistance to chloramphenicol and erythromycin (2,10). In this study, we selected and evaluated seven open reading frames (ORFs) with similarity to staphylococcal MDR pumps from the Staphylococcus aureus strain NCTC8325 genome for their transcription and drug resistance levels in mutant QT21.…”