Anti-biofilm activity and synergism of novel thiazole compounds with glycopeptide antibiotics against multidrug-resistant Staphylococci

Younis

et al. 2017

J. Med. Chem.

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The emergence of antibiotic-resistant bacterial species, such as vancomycin-resistant enterococci (VRE), necessitates the development of new antimicrobials. Here, we investigate the spectrum of antibacterial activity of three phenylthiazole-substituted aminoguanidines. These compounds possess potent activity against VRE, inhibiting growth of clinical isolates at concentrations as low as 0.5 μg/mL. The compounds exerted a rapid bactericidal effect, targeting cell wall synthesis. Transposon mutagenesis suggested three possible targets: YubA, YubB (undecaprenyl diphosphate phosphatase (UPPP)) and YubD. Both UPPP as well as undecaprenyl diphosphate synthase were inhibited by compound 1. YubA and YubD are annotated as transporters and may also be targets since 1 collapsed the proton motive force in membrane vesicles. Using Caenorhabditis elegans, we demonstrate that two compounds (1, 3, at 20 μg/mL) retain potent activity in vivo, significantly reducing the burden of VRE in infected worms. Taken altogether, the results indicate that compounds 1 and 3 warrant further investigation as novel antibacterial agents against drug-resistant enterococci.

Section: Methodsmentioning

confidence: 99%

Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity in Vitro and in Vivo against Vancomycin-Resistant Enterococci

Younis

et al. 2017

J. Med. Chem.

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“…The ability of auranofin to disrupt adherent staphylococcal biofilm was analysed using the microtitre dish biofilm formation assay [2,27]. Staphylococcus aureus ATCC 6538 and Staphylococcus epidermidis ATCC 35984 were inoculated in TSB supplemented with 1% glucose and were transferred to the wells of a 96-well tissue culture treated plate (CELLTREAT Scientific, Shirley, MA).…”

Section: Methodsmentioning

confidence: 99%

Repurposing auranofin for the treatment of cutaneous staphylococcal infections

Thangamani

International Journal of Antimicrobial Agents

Abushahba

et al. 2016

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The scourge of multidrug-resistant bacterial infections necessitates the urgent development of novel antimicrobials to address this public health challenge. Drug repurposing is a proven strategy to discover new antimicrobial agents; given that these agents have undergone extensive toxicological and pharmacological analysis, repurposing is an effective method to reduce the time, cost and risk associated with traditional antibiotic innovation. In this study, the in vitro and in vivo antibacterial activities of an antirheumatic drug, auranofin, was investigated against multidrug-resistant Staphylococcus aureus. The results indicated that auranofin possesses potent antibacterial activity against all tested strains of S. aureus, including meticillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), with minimum inhibitory concentrations (MICs) ranging from 0.0625 μg/mL to 0.125 μg/mL. In vivo, topical auranofin proved superior to conventional antimicrobials, including fusidic acid and mupirocin, in reducing the mean bacterial load in infected wounds in a murine model of MRSA skin infection. In addition to reducing the bacterial load, topical treatment of auranofin greatly reduced the production of inflammatory cytokines, including tumour necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), in infected skin lesions. Moreover, auranofin significantly disrupted established in vitro biofilms of S. aureus and Staphylococcus epidermidis, more so than the traditional antimicrobials linezolid and vancomycin. Taken together, these results support that auranofin has potential to be repurposed as a topical antimicrobial agent for the treatment of staphylococcal skin and wound infections.

“…[8] Aliquots (5 mL) of the bacterial suspension were divided into microcentrifuge tubes and tested compounds (at ½ × MIC) were introduced into each tube. After sitting at room temperature for 30 minutes, samples (1 mL) from each tube were transferred to a new centrifuge tube prior to addition of a subinhibitory concentration of either vancomycin (at a concentration equivalent to 128 μg/mL).…”

Section: Methodsmentioning

confidence: 99%

“…More importantly, the oxadiazole-containing analogues lost one unique advantage over vancomycin, their rapid bactericidal activity against MRSA. [8] The overall result was none of the previously synthesized phenylthiazoles were able to reach the intracellular niches where MRSA harbors in a sufficient concentration either due to poor solubility/permeability, moderate antibacterial effect and/or slow bactericidal mode of action (Figure 1S for 1 st generation phenylthiazoles & Figure 2S for 2 nd generation phenylthiazoles).…”

Section: Introductionmentioning

confidence: 99%

Arylthiazole antibiotics targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA) that interfere with bacterial cell wall synthesis

Eid

Elsebaei

European Journal of Medicinal Chemistry

et al. 2017

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The promising antibacterial potency of arylthiazole antibiotics is offset by their limited activity against intracellular bacteria (namely methicillin-resistant Staphylococcus aureus (MRSA)), similar to many clinically-approved antibiotics. The failure to target these hidden pathogens is due to the compounds’ lack of proper characteristics to accumulate intracellularly. Fine tuning of the size and polar-surface-area of the linking heteroaromatic ring provided a new series of 5-thiazolylarylthiazoles with balanced properties that allow them to sufficiently cross and accumulate inside macrophages infected with MRSA. The most promising compound 4i exhibited rapid bactericidal activity, good metabolic stability and produced over 80% reduction of intracellular MRSA in infected macrophages.