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Highly Active Small Aminated Quinolinequinones against Drug-Resistant Staphylococcus aureus and Candida albicans.

ABSTRACT: Two subseries of aminated quinolinequinones (AQQs, AQQ1-16) containing electron-withdrawing group (EWG) or electron-donating group (EDG) in aryl amine moiety were successfully synthesized. Antimicrobial activity assessment indicates that some of the AQQs (AQQ8-10 and AQQ12-14) with an EDG in aryl amine exhibited strong antibacterial activity against Gram-positive bacterial strains, including Staphylococcus aureus (ATCC^® 29213) and Enterococcus faecalis (ATCC^® 29212). In contrast, AQQ4 with an EWG in aryl amine displayed excellent antifungal activity against fungi Candida albicans (ATCC^® 10231) with a MIC value of 1.22 μg/mL. To explore the mode of action, the selected AQQs (AQQ4 and AQQ9) were further evaluated in vitro to determine their antimicrobial activity against each of 20 clinically obtained resistant strains of Gram-positive bacteria by performing antibiofilm activity assay and time-kill curve assay. In addition, in silico studies were carried out to determine the possible mechanism of action observed in vitro. The data obtained from these experiments suggests that these molecules could be used to target pathogens in different modes of growth, such as planktonic and biofilm.

SUBMITTER: Yıldırım H

PROVIDER: S-EPMC9104734 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Highly Active Small Aminated Quinolinequinones against Drug-Resistant Staphylococcus aureus and Candida albicans.

Yıldırım Hatice H Bayrak Nilüfer N Yıldız Mahmut M Yılmaz Fatıma Nur FN Mataracı-Kara Emel E Shilkar Deepak D Jayaprakash Venkatesan V TuYuN Amaç Fatih AF

Molecules (Basel, Switzerland) 20220503 9

Two subseries of aminated quinolinequinones (AQQs, AQQ1-16) containing electron-withdrawing group (EWG) or electron-donating group (EDG) in aryl amine moiety were successfully synthesized. Antimicrobial activity assessment indicates that some of the AQQs (AQQ8-10 and AQQ12-14) with an EDG in aryl amine exhibited strong antibacterial activity against Gram-positive bacterial strains, including Staphylococcus aureus (ATCC® 29213) and Enterococcus ...[more]

PMID: 35566274

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Project description:Biofilm-associated polymicrobial infections, particularly those involving fungi and bacteria, are responsible for significant morbidity and mortality and tend to be challenging to treat. Candida albicans and Staphylococcus aureus specifically are considered leading opportunistic fungal and bacterial pathogens, respectively, mainly due to their ability to form biofilms on catheters and indwelling medical devices. However, the impact of mixed-species biofilm growth on therapy remains largely understudied. In this study, we investigated the influence of C. albicans secreted cell wall polysaccharides on the response of S. aureus to antibacterial agents in biofilm. Results demonstrated significantly enhanced tolerance for S. aureus to drugs in the presence of C. albicans or its secreted cell wall polysaccharide material. Fluorescence confocal time-lapse microscopy revealed impairment of drug diffusion through the mixed biofilm matrix. Using C. albicans mutant strains with modulated cell wall polysaccharide expression, exogenous supplementation, and enzymatic degradation, the C. albicans-secreted β-1,3-glucan cell wall component was identified as the key matrix constituent providing the bacteria with enhanced drug tolerance. Further, antibody labeling demonstrated rapid coating of the bacteria by the C. albicans matrix material. Importantly, via its effect on the fungal biofilm matrix, the antifungal caspofungin sensitized the bacteria to the drugs. Understanding such symbiotic interactions with clinical relevance between microbial species in biofilms will greatly aid in overcoming the limitations of current therapies and in defining potential new targets for treating polymicrobial infections. The fungus Candida albicans and the bacterium Staphylococcus aureus are important microbial pathogens responsible for the majority of infections in hospitalized patients and are often coisolated from a host. In this study, we demonstrated that when grown together, the fungus provides the bacterium with enhanced tolerance to antimicrobial drugs. This process was mediated by polysaccharides secreted by the fungal cell into the environment. The biofilm matrix formed by these polysaccharides prevented penetration by the drugs and provided the bacteria with protection. Importantly, we show that by inhibiting the production of the fungal polysaccharides, a specific antifungal agent indirectly sensitized the bacteria to antimicrobials. Understanding the therapeutic implications of the interactions between these two diverse microbial species will aid in overcoming the limitations of current therapies and in defining new targets for treating complex polymicrobial infections.

Project description:BackgroundGiven the rising occurrence of antibiotic resistance due to the existence and ongoing development of resistant bacteria and phenotypes, the identification of new treatments and sources of antimicrobial agents is of utmost urgency. An important strategy for tackling bacterial resistance involves the utilization of drug combinations, and natural products derived from plants hold significant potential as a rich source of bioactive compounds that can act as effective adjuvants. This study, therefore, aimed to assess the antibacterial potential and the chemical composition of Miconia albicans, a Brazilian medicinal plant used to treat various diseases.MethodsEthanolic extracts from leaves and stems of M. albicans were obtained and subsequently partitioned to give the corresponding hexane, chloroform, ethyl acetate, and hydromethanolic phases. All extracts and phases had their chemical constitution investigated by HPLC-DAD-MS/MS and GC-MS and were assessed for their antibiofilm and antimicrobial efficacy against Staphylococcus aureus. Furthermore, their individual effects and synergistic potential in combination with antibiotics were examined against clinical strains of both S. aureus and Acinetobacter baumannii. In addition, 10 isolated compounds were obtained from the leaves phases and used for confirmation of the chemical profiles and for antibacterial assays.ResultsBased on the chemical profile analysis, 32 compounds were successfully or tentatively identified, including gallic and ellagic acid derivatives, flavonol glycosides, triterpenes and pheophorbides. Extracts and phases obtained from the medicinal plant M. albicans demonstrated synergistic effects when combined with the commercial antibiotics ampicillin and ciprofloxacin, against multi-drug resistant bacteria S. aureus and A. baumannii, restoring their antibacterial efficacy. Extracts and phases also exhibited antibiofilm property against S. aureus. Three key compounds commonly found in the samples, namely gallic acid, quercitrin, and corosolic acid, did not exhibit significant antibacterial activity when assessed individually or in combination with antibiotics against clinical bacterial strains.ConclusionsOur findings reveal that M. albicans exhibits remarkable adjuvant potential for enhancing the effectiveness of antimicrobial drugs against resistant bacteria.

Project description:Candida albicans form biofilm by associating with biotic and abiotic surfaces. Biofilm formation by C. albicans is relevant and significant as the organisms residing within, gain resistance to conventional antimycotics and are therefore difficult to treat. This study targeted the potential of spice-based antimycotics to control C. albicans biofilms. Ten clinical isolates of C. albicans along with a standard culture MTCC-3017 (ATCC-90028) were screened for their biofilm-forming ability. C. albicans M-207 and C. albicans S-470 were identified as high biofilm formers by point inoculation on Trypticase Soy Agar (TSA) medium as they formed a lawn within 16 h and exhibited resistance to fluconazole and caspofungin at 25 mcg and 8 mcg respectively. Aqueous and organic spice extracts were screened for their antimycotic activity against C. albicans M-207 and S-470 by agar and disc diffusion and a Zone of Inhibition was observed. Minimal Inhibitory Concentration was determined based on growth absorbance and cell viability measurements. The whole aqueous extract of garlic inhibited biofilms of C. albicans M-207, whereas whole aqueous extracts of garlic, clove, and Indian gooseberry were effective in controlling C. albicans S-470 biofilm within 12 h of incubation. The presence of allicin, ellagic acid, and gallic acid as dominant compounds in the aqueous extracts of garlic, clove, and Indian gooseberry respectively was determined by High-Performance Thin Layer Chromatography and Liquid Chromatography-Mass Spectrometry. The morphology of C. albicans biofilm at different growth periods was also determined through bright field microscopy, phase contrast microscopy, and fluorescence microscopy. The results of this study indicated that the alternate approach in controlling high biofilm-forming, multi-drug resistant clinical isolates of C. albicans M-207 and S-470 using whole aqueous extracts of garlic, clove, and Indian gooseberry is a safe, potential, and cost-effective one that can benefit the health care needs with additional effective therapeutics to treat biofilm infections.

Dataset Information

Highly Active Small Aminated Quinolinequinones against Drug-Resistant Staphylococcus aureus and Candida albicans.

Publications

Highly Active Small Aminated Quinolinequinones against Drug-Resistant <i>Staphylococcus aureus</i> and <i>Candida albicans</i>.

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