Resistance against antimicrobial peptides is independent of Escherichia coli AcrAB, Pseudomonas aeruginosa MexAB and Staphylococcus aureus NorA efflux pumps
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Most clinical isolates that exhibit a multi-drug resistant phenotype owe that resistance to over-expressed efflux pumps. Compounds that are efflux pump inhibitors (EPIs) reduce or reverse resistance to antibiotics to which the bacterial strain is initially resistant. We have evaluated non-antibiotics to reduce resistance of commonly encountered bacterial pathogens to antibiotics.The effect of non-antibiotics on the susceptibility of bacteria to antibiotics was conducted by minimum inhibition concentration determinations of the antibiotic in the absence and presence of the non-antibiotic.Non-antibiotics such as chlorpromazine, amitryptiline and trans-chlorprothixene are shown to reduce or reverse resistance of a variety of bacteria to antibiotics.The results suggest that non-antibiotics may serve as adjuncts to conventional antibiotics for the therapy of problematic antibiotic infections caused by bacteria that owe their resistance to over-expressed efflux pumps.
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Bacteria have a complex and lengthy evolutionary history of antibiotic resistance. For millions of years, bacteria have evolved a gene pool filled with multiple drug resistant genes. However, for the past 50 years, bacteria have been mutating and evolving vigorously and rapidly. Those 50 years predate to the time of the first use of antibiotic drugs in the 1940s. Since the 1940s, with the wide-spread use of the first antibiotic, penicillin, bacteria have effectively developed resistance to multiple antibiotic drugs. Bacteria develop antibiotic resistance after acquiring antibiotic resistant genes from conjugation and a horizontal transfer of those genes. Bacteria also have innate properties, structure, and functions that can increase their resistance of antibiotics. Bacteria cells can mutate its genes and block the binding of antibiotic drugs to its DNA. If the bacteria effectively impede the activity of an antibiotic through a DNA mutation, then the same mutation is shared with other bacterial cell strains through horizontal transfer. Antibiotics can be expelled from bacteria cells by efflux pumps called AcrBC-Tolc channels from the resistance-nodulation division (RND) family. Targeting the cell metabolism or the expression of efflux pumps may deter or impede the proliferation of antibiotic resistance. Researchers cultured E. tarda with glucose and alanine, and the uptake of kanamycin increased, eliminating approximately 3,000 times the amount of MDR bacterial cells compared to the cells only treated with kanamycin. Another researcher named Dr. Li mutated a gene of the AcrAB-Tolc binding site, forming a replacement for the highly non-polar phenylalanine amino acid residue with an alanine. His mutagenesis of the efflux pumps binding sites for AcrAB-Tolc inhibited the exit of antibiotics through the AcrAB-Tolc efflux pumps. Therefore, the review serves to discuss the new, novel, and current methods for reducing the spread of antibiotic resistant bacteria by targeting bacterial cell metabolism and its antibiotic resistant genes.
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Multidrug-resistant (MDR) Pseudomonas aeruginosa is a global threat to public health. This study aimed to determine biofilms and efflux pump regulatory gene (mexR) in MDR P. aeruginosa isolates.A total of 42 fecal samples of aquatic migratory birds collected during hunting season in Egypt were evaluated for the detection of P. aeruginosa according to standard culture-based methods. The antibiotic susceptibility of P. aeruginosa strains was evaluated using disk diffusion methods. The biofilm formation ability of the isolates was phenotypically determined using a colorimetric microtitration plate assay. Polymerase chain reaction amplification was performed to detect biofilm genes (PelA and PslA) and mexR.In total, 19 isolates (45.2%) were recovered from the 42 fecal samples of migratory birds. All isolates were identified as MDR P. aeruginosa, and 78.9% of the strains produced biofilms at different degrees. Molecular detection of biofilm extracellular polymeric substances revealed that PelA was the most predominant gene in the biofilm-producing isolates, followed by PslA. mexR was detected in 63.2% of MDR P. aeruginosa isolates, and its prevalence was higher in non-biofilm-producing strains (75%) than in biofilm-producing strains (60%).Antibiotic resistance in P. aeruginosa isolates recovered from migratory birds through various mechanisms is a major public and animal health problem. It is important to consider the significance of migratory birds in disease transmission.
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Antibiotic-resistant bacteria pose an ever-increasing therapeutic problem. The ways whereby bacteria circumvent drug action are many and varied, ranging from intrinsic impermeability to acquired resistance (involving plasmids, transposons and mutations). Antibiotics may be unable to reach susceptible target sites, they may be enzymatically inactivated, modified or expelled or mutations may arise such as to render the target sites insusceptible. Mechanisms of bacterial resistance to biocides are less well understood but cellular impermeability is a major factor. Plasmid-mediated efflux of cationic antiseptics in antibiotic-resistant Staphylococcus aureus strains has been demonstrated but its role in the resistance of these organisms to the biocide concentrations used in clinical practice is unclear. An association between resistance to antibiotics and biocides in Gram-negative bacteria has also been observed but it is often difficult at present to reach definite conclusions about genetic linkages between antibiotic resistance and biocide resistance.
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Gram‐negative bacteria remain clinically important pathogens in both hospital and community settings. Recent research indicates that efflux pumps play a prominent role in the multidrug resistance of Pseudomonas aeruginosa and many other gram‐negative bacteria. Four multidrug efflux pump systems have been well characterized in P. aeruginosa : MexA‐MexB‐OprM, MexC‐MexD‐OprJ, MexE‐MexF‐OprN, and MexX‐MexY‐OprM. These efflux pumps have different substrate specificities, and their production and activity can be increased by many factors commonly present in infections (e.g., high inocula of bacteria, low pH, and stationary‐phase growth). Moreover, fluoroquinolone antibiotics can commonly select mutants that constitutively overproduce Mex‐Opr efflux pump systems. Based on most recent studies, the prevalence of efflux pump overproduction in clinical strains of P. aeruginosa may range from 14–75%. The best treatment for infections caused by bacteria that overproduce efflux pumps is unknown, but pharmacodynamic optimization of antibiotics and the use of antibiotic combinations that are substrates for different pump systems may represent reasonable strategies until more data are available.
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In this study, we systematically investigated the resistance mechanisms to beta-lactams, aminoglycosides, and fluoroquinolones of 120 bacteremic strains of Pseudomonas aeruginosa. Pulsed-field gel electrophoresis genotyping showed that 97 of these strains were represented by a single isolate, 10 by 2 and 1 by 3 clonally related isolates, respectively. Seventy-five percent (90 out of 120) of the bacteremic P. aeruginosa strains displayed a significant resistance to one or more of the tested antimicrobials (up to 11 for 1 strain). These strains were found to harbor a great diversity of resistance mechanisms (up to 7 in 1 strain), leading to various levels of drug resistance. Interestingly, 11 and 36% of the isolates appeared to overproduce the MexAB-OprM and MexXY-OprM efflux systems, respectively. Altogether, our results show that P. aeruginosa may accumulate intrinsic (overproduction of cephalosporinase AmpC, increased drug efflux, fluoroquinolone target mutations, and deficient production of porin OprD) and exogenous (production of secondary beta-lactamases and aminoglycoside-modifying enzymes) resistance mechanisms without losing its ability to generate severe bloodstream infections. Consequently, clinicians should be aware that multidrug-resistant P. aeruginosa may remain fully pathogenic.
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Objective To screen gyrA mutant and multidrug resistance (MDR) efflux pump (MexAB-OprM) of Pseudomonas aeruginosa (Pa) and to identify the contribution of gyrA mutant and MDR efflux pump to bacterial drug resistance during the formation of Pa biofilms. Methods The strains of gyrA mutant and MDR efflux pump were clinical isolates and detected by PCR. Tri-relative hybridization experiments were performed to transfer report gene of GFP into sensitive Pa strains. The formation of bacterial biofilms was observed by scanning electron microscope followed by analysis of bacterial survival rate. Results The fluorescent strains with pGFPuv could form mature biofilms on Teflon surface. Over a period of 72 h, the survival rate of biofilm bacteria was more than 50% in its′ MBC of ciprofloxacin. Conclusion The express of gyrA mutation and MDR efflux played major roles in Pa resistance during the initial stage of biofilm development. But after 72 h of incubation, there was no significant difference between mutants and sensitive strains in terms of survival rate.
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Bacteria have a complex and lengthy evolutionary history of antibiotic resistance. For millions of years, bacteria have evolved a gene pool filled with multiple drug resistant genes. However, for the past 50 years, bacteria have been mutating and evolving vigorously and rapidly. Those 50 years predate to the time of the first use of antibiotic drugs in the 1940s. Since the 1940s, with the wide-spread use of the first antibiotic, penicillin, bacteria have effectively developed resistance to multiple antibiotic drugs. Bacteria develop antibiotic resistance after acquiring antibiotic resistant genes from conjugation and a horizontal transfer of those genes. Bacteria also have innate properties, structure, and functions that can increase their resistance of antibiotics. Bacteria cells can mutate its genes and block the binding of antibiotic drugs to its DNA. If the bacteria effectively impede the activity of an antibiotic through a DNA mutation, then the same mutation is shared with other bacterial cell strains through horizontal transfer. Antibiotics can be expelled from bacteria cells by efflux pumps called AcrBC-Tolc channels from the resistance-nodulation division (RND) family. Targeting the cell metabolism or the expression of efflux pumps may deter or impede the proliferation of antibiotic resistance. Researchers cultured E. tarda with glucose and alanine, and the uptake of kanamycin increased, eliminating approximately 3,000 times the amount of MDR bacterial cells compared to the cells only treated with kanamycin. Another researcher named Dr. Li mutated a gene of the AcrAB-Tolc binding site, forming a replacement for the highly non-polar phenylalanine amino acid residue with an alanine. His mutagenesis of the efflux pumps binding sites for AcrAB-Tolc inhibited the exit of antibiotics through the AcrAB-Tolc efflux pumps. Therefore, the review serves to discuss the new, novel, and current methods for reducing the spread of antibiotic resistant bacteria by targeting bacterial cell metabolism and its antibiotic resistant genes.
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Kanamycin
Horizontal Gene Transfer
Bacterial Genetics
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Multidrug efflux systems of the resistance-nodulation-cell division family play a crucial role in resistance of Pseudomonas aeruginosa to a large variety of antibiotics. Here, we investigated the role of clinically relevant efflux pumps MexAB- OprM, MexCD- OprJ, and MexXY- OprM in resistance against different cationic antimicrobial peptides (AMPs). Our results indicate that a knock-out in efflux pump MexXY-OprM increased susceptibility to some AMPs by two- to eightfold. Our data suggest a contribution of MexXY-OprM in resistance to certain AMPs in P. aeruginosa, which should be considered in the future development of new and highly active antimicrobial peptides to fight multidrug resistant infections.
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