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Emerging antibiotic resistance in bacteria endorses the failure of existing drugs with chronic illness, complicated treatment, and ever-increasing expenditures. Bacteria acquire the nature to adapt to starving conditions, abiotic stress, antibiotics, and our immune defense mechanism due to its swift evolution. The intense and inappropriate use of antibiotics has led to the development of multidrug-resistant (MDR) strains of bacteria. Phytochemicals can be used as an alternative for complementing antibiotics due to their variation in metabolic, genetic, and physiological fronts as well as the rapid evolution of resistant microbes and lack of tactile management. Several phytochemicals from diverse groups, including alkaloids, phenols, coumarins, and terpenes, have effectively proved their inhibitory potential against MDR pathogens through their counter-action towards bacterial membrane proteins, efflux pumps, biofilms, and bacterial cell-to-cell communications, which are important factors in promoting the emergence of drug resistance. Plant extracts consist of a complex assortment of phytochemical elements, against which the development of bacterial resistance is quite deliberate. This review emphasizes the antibiotic resistance mechanisms of bacteria, the reversal mechanism of antibiotic resistance by phytochemicals, the bioactive potential of phytochemicals against MDR, and the scientific evidence on molecular, biochemical, and clinical aspects to treat bacterial pathogenesis in humans. Moreover, clinical efficacy, trial, safety, toxicity, and affordability investigations, current status and developments, related demands, and future prospects are also highlighted.

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Quorum sensing (QS) is a signaling mechanism governed by bacteria used to converse at inter- and intra-species levels through small self-produced chemicals called N-acylhomoserine lactones (AHLs). Through QS, bacteria regulate and organize the virulence factors' production, including biofilm formation. AHLs can be degraded by an action called quorum quenching (QQ) and hence QQ strategy can effectively be employed to combat biofilm-associated bacterial pathogenesis. The present study aimed to identify novel bacterial species with QQ potential. Screening of Palk Bay marine sediment bacteria for QQ activity ended up with the identification of marine bacterial isolate 28 (MSB-28), which exhibited a profound QQ activity against QS biomarker strain Chromobacterium violaceum ATCC 12472. The isolate MSB-28 was identified as Psychrobacter sp. through 16S-rRNA sequencing. Psychrobacter sp. also demonstrated a pronounced activity in controlling the biofilm formation in different bacteria and biofilm-associated virulence factors' production in P. aeruginosa PAO1. Solvent extraction, heat inactivation, and proteinase K treatment assays clearly evidence the enzymatic nature of the bioactive lead. Furthermore, AHL's lactone ring cleavage was confirmed with experiments including ring closure assay and chromatographic analysis, and thus the AHL-lactonase enzyme production in Psychrobacter sp. To conclude, this is the first report stating the AHL-lactonase mediated QQ activity from marine sediment bacteria Psychrobacter sp. Future work deals with the characterization, purification, and mass cultivation of the purified protein and should pave the way to assessing the feasibility of the identified protein in controlling QS and biofilm-mediated multidrug resistant bacterial infections in mono or multi-species conditions.

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Staphylococcus epidermidis (SE) is an opportunistic nosocomial pathogen that accounts for recalcitrant device-related infections worldwide. Owing to the growing interest in plants and their secondary metabolites targeting bacterial adhesion, this study was intended to uncover the anti-biofilm potential of Hemidesmus indicus and its major constituent 2-hydroxy-4-methoxybenzaldehyde (HMB) against SE. The minimum biofilm inhibitory concentration (MBIC) of H. indicus root extract and HMB were found to be 500 and 250 µg ml-1, respectively. The results of time-dependent biofilm inhibition and mature biofilm disruption assays confirmed that HMB targets initial cell adhesion. Furthermore, interference by HMB in the expression of adhesin genes (icaA, aap and bhp) and biofilm components was associated with an increased susceptibility of SE to oxidative stress and antibiotics. To conclude, this study reports for the first time HMB as a potential drug against SE biofilms.

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In humans, the occurrence of bacterial communities in the form of biofilm is considered as a major intrinsic factor accountable for a variety of stubborn infections. Staphylococcus aureus and S. epidermidis have gained considerable attention in clinical settings owing to the formation of intractable and long-lasting biofilms in medical device. The current study has been designed to explain the biofilm inhibitory efficacy of geraniol and cefotaxime combination (GCC) against S. epidermidis and methicillin-resistant S. aureus (MRSA). Biofilm biomass quantification assay was performed to evaluate the antibiofilm activity of GCC against S. epidermidis and MRSA. The minimal biofilm inhibitory concentration of GCC was found to be 100 µg/ml of geraniol and 2 µg/ml of cefotaxime. Further, microscopic analyses ascertained the devastating potential of GCC on the test pathogens' biofilm formation. Besides biofilm inhibition, GCC also suppressed the production of extracellular polymeric substance, slime and staphyloxanthin. More, GCC significantly increased the susceptibility of the test pathogens towards human blood. Further, the results of real time PCR analysis and in vivo assay using Caenorhabditis elegans unveiled the anti-biofilm potentials of GCC. Thus, the present study demonstrates the significant use of polytherapy treatment approaches to overcome the biofilm associated infections of Staphylococcus spp.

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Urinary tract infection is caused primarily by the quorum sensing (QS)-dependent biofilm forming ability of uropathogens. In the present investigation, an anti-quorum sensing (anti-QS) agent curcumin from Curcuma longa (turmeric) was shown to inhibit the biofilm formation of uropathogens, such as Escherichia coli, Pseudomonas aeruginosa PAO1, Proteus mirabilis and Serratia marcescens, possibly by interfering with their QS systems. The antibiofilm potential of curcumin on uropathogens as well as its efficacy in disturbing the mature biofilms was examined under light microscope and confocal laser scanning microscope. The treatment with curcumin was also found to attenuate the QS-dependent factors, such as exopolysaccharide production, alginate production, swimming and swarming motility of uropathogens. Furthermore, it was documented that curcumin enhanced the susceptibility of a marker strain and uropathogens to conventional antibiotics.

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The increasing occurrence of disease outbreaks caused by Vibrio spp. and the emergence of antibiotic resistance has led to a growing interest in finding alternative strategies to prevent vibriosis. Since the pathogenicity of vibrios is controlled in part by quorum-sensing (QS) system, interfering with this mechanism would prevent the pathogenicity of vibrios without developing resistance. Hence, a non-toxic phytochemical curcumin from Curcuma longa was assessed for its potential in reducing the production of QS-dependent virulence factors in Vibrio spp. The obtained results evidenced 88% reduction in bioluminescence of Vibrio harveyi by curcumin. Further, curcumin exhibited a significant inhibition in alginate, exopolysaccharides, motility, biofilm development and other virulence factors production in Vibrio parahaemolyticus, Vibrio vulnificus and V. harveyi. In in vivo analysis, curcumin enhanced the survival rate of Artemia nauplii up to 67% against V. harveyi infection by attenuating its QS-mediated virulence.

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