# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 4434 | 0 | 1.0000 | Battle against Vancomycin-Resistant Bacteria: Recent Developments in Chemical Strategies. Vancomycin, a natural glycopeptide antibiotic, was used as the antibiotic of last resort for the treatment of multidrug-resistant Gram-positive bacterial infections. However, almost 30 years after its use, resistance to vancomycin was first reported in 1986 in France. This became a major health concern, and alternative treatment strategies were urgently needed. New classes of molecules, including semisynthetic antibacterial compounds and newer generations of the previously used antibiotics, were developed. Semisynthetic derivatives of vancomycin with enhanced binding affinity, membrane disruption ability, and lipid binding properties have exhibited promising results against both Gram-positive and Gram-negative bacteria. Various successful approaches developed to overcome the acquired resistance in Gram-positive bacteria, intrinsic resistance in Gram-negative bacteria, and other forms of noninherited resistance to vancomycin have been discussed in this Perspective. | 2019 | 30404451 |
| 4442 | 1 | 0.9998 | Mechanisms of antimicrobial resistance in bacteria. The treatment of bacterial infections is increasingly complicated by the ability of bacteria to develop resistance to antimicrobial agents. Antimicrobial agents are often categorized according to their principal mechanism of action. Mechanisms include interference with cell wall synthesis (eg, beta-lactams and glycopeptide agents), inhibition of protein synthesis (macrolides and tetracyclines), interference with nucleic acid synthesis (fluoroquinolones and rifampin), inhibition of a metabolic pathway (trimethoprim-sulfamethoxazole), and disruption of bacterial membrane structure (polymyxins and daptomycin). Bacteria may be intrinsically resistant to > or =1 class of antimicrobial agents, or may acquire resistance by de novo mutation or via the acquisition of resistance genes from other organisms. Acquired resistance genes may enable a bacterium to produce enzymes that destroy the antibacterial drug, to express efflux systems that prevent the drug from reaching its intracellular target, to modify the drug's target site, or to produce an alternative metabolic pathway that bypasses the action of the drug. Acquisition of new genetic material by antimicrobial-susceptible bacteria from resistant strains of bacteria may occur through conjugation, transformation, or transduction, with transposons often facilitating the incorporation of the multiple resistance genes into the host's genome or plasmids. Use of antibacterial agents creates selective pressure for the emergence of resistant strains. Herein 3 case histories-one involving Escherichia coli resistance to third-generation cephalosporins, another focusing on the emergence of vancomycin-resistant Staphylococcus aureus, and a third detailing multidrug resistance in Pseudomonas aeruginosa-are reviewed to illustrate the varied ways in which resistant bacteria develop. | 2006 | 16813980 |
| 9521 | 2 | 0.9998 | Next-generation strategy for treating drug resistant bacteria: Antibiotic hybrids. Resistance against nearly all antibiotics used clinically have been documented in bacteria. There is an ever-increasing danger caused by multidrug-resistant Gram-negative bacteria in both hospital and community settings. In Gram-negative bacteria, intrinsic resistance to currently available antibiotics is mainly due to overexpressed efflux pumps which are constitutively present and also presence of protective outer membrane. Combination therapy, i.e., use of two or more antibiotics, was thought to be an effective strategy because it took advantage of the additive effects of multiple antimicrobial mechanisms, lower risk of resistance development and lower mortality and improved clinical outcome. However, none of the benefits were seen in in vivo studies. Antibiotic hybrids are being used to challenge the growing drug resistance threat and increase the usefulness of current antibiotic arsenal. Antibiotic hybrids are synthetic constructs of two molecules which are covalently linked. These could be two antibiotics or antibiotic with an adjuvant (efflux pump inhibitor, siderophore, etc.) which increases the access of the antibiotics to the target. The concepts, developments and challenges in the future use of antibiotic hybrids are discussed here. Majority of the studies have been conducted on fluoroquinolones and aminoglycosides molecules. The antibiotic tobramycin has the property to enhance the action of antimicrobial agents against which the multidrug-resistant Gram-negative bacteria were earlier resistant, and thus potentiating the action of legacy antibiotics. Antibiotic hybrids may have a role as the silver bullet in Gram-negative bacteria to overcome drug resistance as well as extend the spectrum of existing antibiotics. | 2019 | 31219074 |
| 4441 | 3 | 0.9998 | Mechanisms of antimicrobial resistance in bacteria. The treatment of bacterial infections is increasingly complicated by the ability of bacteria to develop resistance to antimicrobial agents. Antimicrobial agents are often categorized according to their principal mechanism of action. Mechanisms include interference with cell wall synthesis (e.g., beta-lactams and glycopeptide agents), inhibition of protein synthesis (macrolides and tetracyclines), interference with nucleic acid synthesis (fluoroquinolones and rifampin), inhibition of a metabolic pathway (trimethoprim-sulfamethoxazole), and disruption of bacterial membrane structure (polymyxins and daptomycin). Bacteria may be intrinsically resistant to > or =1 class of antimicrobial agents, or may acquire resistance by de novo mutation or via the acquisition of resistance genes from other organisms. Acquired resistance genes may enable a bacterium to produce enzymes that destroy the antibacterial drug, to express efflux systems that prevent the drug from reaching its intracellular target, to modify the drug's target site, or to produce an alternative metabolic pathway that bypasses the action of the drug. Acquisition of new genetic material by antimicrobial-susceptible bacteria from resistant strains of bacteria may occur through conjugation, transformation, or transduction, with transposons often facilitating the incorporation of the multiple resistance genes into the host's genome or plasmids. Use of antibacterial agents creates selective pressure for the emergence of resistant strains. Herein 3 case histories-one involving Escherichia coli resistance to third-generation cephalosporins, another focusing on the emergence of vancomycin-resistant Staphylococcus aureus, and a third detailing multidrug resistance in Pseudomonas aeruginosa--are reviewed to illustrate the varied ways in which resistant bacteria develop. | 2006 | 16735149 |
| 4433 | 4 | 0.9998 | The Vancomycin Group of Antibiotics and the Fight against Resistant Bacteria. A last line of defence against "superbugs" are the vancomycin group antibiotics. This review describes the determination of their mode of action, and a mechanism of resistance to them. Remarkably, this mechanism of resistance can be overcome without directly modifying the binding site of the antibiotics for the cell-wall precursors of pathogenic bacteria. | 1999 | 29711719 |
| 4254 | 5 | 0.9998 | The forgotten Gram-negative bacilli: what genetic determinants are telling us about the spread of antibiotic resistance. Gram-negative bacilli have become increasingly resistant to antibiotics over the past 2 decades due to selective pressure from the extensive use of antibiotics in the hospital and community. In addition, these bacteria have made optimum use of their innate genetic capabilities to extensively mutate structural and regulatory genes of antibiotic resistance factors, broadening their ability to modify or otherwise inactivate antibiotics in the cell. The great genetic plasticity of bacteria have permitted the transfer of resistance genes on plasmids and integrons between bacterial species allowing an unprecedented dissemination of genes leading to broad-spectrum resistance. As a result, many Gram-negative bacilli possess a complicated set of genes encoding efflux pumps, alterations in outer membrane lipopolysaccharides, regulation of porins and drug inactivating enzymes such as beta-lactamases, that diminish the clinical utility of today's antibiotics. The cross-species mobility of these resistance genes indicates that multidrug resistance will only increase in the future, impacting the efficacy of existing antimicrobials. This trend toward greater resistance comes at a time when very few new antibiotics have been identified capable of controlling such multi-antibiotic resistant pathogens. The continued dissemination of these resistance genes underscores the need for new classes of antibiotics that do not possess the liability of cross-resistance to existing classes of drugs and thereby having diminished potency against Gram-negative bacilli. | 2006 | 16359640 |
| 4443 | 6 | 0.9998 | Cellular Studies of an Aminoglycoside Potentiator Reveal a New Inhibitor of Aminoglycoside Resistance. Aminoglycosides are a group of broad-spectrum antibiotics that have been used in the clinic for almost a century. The rapid spread of bacterial genes coding for aminoglycoside-modifying enzymes has, however, dramatically decreased the utility of aminoglycosides. We have previously reported several aminoglycoside potentiators that work by inhibiting aminoglycoside N-6'-acetyltransferase, one of the most common determinants of aminoglycoside resistance. Among these, prodrugs that combine the structure of an aminoglycoside with that of pantothenate into one molecule are especially promising. We report here a series of cellular studies to investigate the activity and mechanism of action of these prodrugs further. Our results reveal a new aminoglycoside resistance inhibitor, as well as the possibility that these prodrugs are transformed into more than one inhibitor in bacteria. We also report that the onset of the potentiators is rapid. Their low cell cytotoxicity, good stability, and potentiation of various aminoglycosides, against both Gram-positive and Gram-negative bacteria, make them interesting compounds for the development of new drugs. | 2018 | 30059603 |
| 4253 | 7 | 0.9998 | Molecular mechanisms of polymyxin resistance and detection of mcr genes. Antibiotic resistance is an ever-increasing global problem. Major commercial antibiotics often fail to fight common bacteria, and some pathogens have become multi-resistant. Polymyxins are potent bactericidal antibiotics against gram-negative bacteria. Known resistance to polymyxin includes intrinsic, mutational and adaptive mechanisms, with the recently described horizontally acquired resistance mechanisms. In this review, we present several strategies for bacteria to develop enhanced resistance to polymyxins, focusing on changes in the outer membrane, efflux and other resistance determinants. Better understanding of the genes involved in polymyxin resistance may pave the way for the development of new and effective antimicrobial agents. We also report novel in silico tested primers for PCR assay that may be able distinguish colistin-resistant isolates carrying the plasmid-encoded mcr genes and will assist in combating the spread of colistin resistance in bacteria. | 2019 | 30439931 |
| 4252 | 8 | 0.9998 | Extreme antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. Cationic antimicrobial peptides and polymyxins are a group of naturally occurring antibiotics that can also possess immunomodulatory activities. They are considered a new source of antibiotics for treating infections by bacteria that are resistant to conventional antibiotics. Members of the genus Burkholderia, which includes various human pathogens, are inherently resistant to antimicrobial peptides. The resistance is several orders of magnitude higher than that of other Gram-negative bacteria such as Escherichia coli, Salmonella enterica, or Pseudomonas aeruginosa. This review summarizes our current understanding of antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. These bacteria possess major and minor resistance mechanisms that will be described in detail. Recent studies have revealed that many other emerging Gram-negative opportunistic pathogens may also be inherently resistant to antimicrobial peptides and polymyxins and we propose that Burkholderia sp. are a model system to investigate the molecular basis of the resistance in extremely resistant bacteria. Understanding resistance in these types of bacteria will be important if antimicrobial peptides come to be used regularly for the treatment of infections by susceptible bacteria because this may lead to increased resistance in the species that are currently susceptible and may also open up new niches for opportunistic pathogens with high inherent resistance. | 2011 | 22919572 |
| 4251 | 9 | 0.9998 | Extreme antimicrobial Peptide and polymyxin B resistance in the genus burkholderia. Cationic antimicrobial peptides and polymyxins are a group of naturally occurring antibiotics that can also possess immunomodulatory activities. They are considered a new source of antibiotics for treating infections by bacteria that are resistant to conventional antibiotics. Members of the genus Burkholderia, which includes various human pathogens, are inherently resistant to antimicrobial peptides. The resistance is several orders of magnitude higher than that of other Gram-negative bacteria such as Escherichia coli, Salmonella enterica, or Pseudomonas aeruginosa. This review summarizes our current understanding of antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. These bacteria possess major and minor resistance mechanisms that will be described in detail. Recent studies have revealed that many other emerging Gram-negative opportunistic pathogens may also be inherently resistant to antimicrobial peptides and polymyxins and we propose that Burkholderia sp. are a model system to investigate the molecular basis of the resistance in extremely resistant bacteria. Understanding resistance in these types of bacteria will be important if antimicrobial peptides come to be used regularly for the treatment of infections by susceptible bacteria because this may lead to increased resistance in the species that are currently susceptible and may also open up new niches for opportunistic pathogens with high inherent resistance. | 2011 | 21811491 |
| 9756 | 10 | 0.9998 | Genomewide identification of genetic determinants of antimicrobial drug resistance in Pseudomonas aeruginosa. The emergence of antimicrobial drug resistance is of enormous public concern due to the increased risk of delayed treatment of infections, the increased length of hospital stays, the substantial increase in the cost of care, and the high risk of fatal outcomes. A prerequisite for the development of effective therapy alternatives is a detailed understanding of the diversity of bacterial mechanisms that underlie drug resistance, especially for problematic gram-negative bacteria such as Pseudomonas aeruginosa. This pathogen has impressive chromosomally encoded mechanisms of intrinsic resistance, as well as the potential to mutate, gaining resistance to current antibiotics. In this study we have screened the comprehensive nonredundant Harvard PA14 library for P. aeruginosa mutants that exhibited either increased or decreased resistance against 19 antibiotics commonly used in the clinic. This approach identified several genes whose inactivation sensitized the bacteria to a broad spectrum of different antimicrobials and uncovered novel genetic determinants of resistance to various classes of antibiotics. Knowledge of the enhancement of bacterial susceptibility to existing antibiotics and of novel resistance markers or modifiers of resistance expression may lay the foundation for effective therapy alternatives and will be the basis for the development of new strategies in the control of problematic multiresistant gram-negative bacteria. | 2009 | 19332674 |
| 4402 | 11 | 0.9998 | Mechanisms of antimicrobial resistance in Stenotrophomonas maltophilia: a review of current knowledge. Introduction: Stenotrophomonas maltophilia is a prototype of bacteria intrinsically resistant to antibiotics. The reduced susceptibility of this microorganism to antimicrobials mainly relies on the presence in its chromosome of genes encoding efflux pumps and antibiotic inactivating enzymes. Consequently, the therapeutic options for treating S. maltophilia infections are limited.Areas covered: Known mechanisms of intrinsic, acquired and phenotypic resistance to antibiotics of S. maltophilia and the consequences of such resistance for treating S. maltophilia infections are discussed. Acquisition of some genes, mainly those involved in co-trimoxazole resistance, contributes to acquired resistance. Mutation, mainly in the regulators of chromosomally-encoded antibiotic resistance genes, is a major cause for S. maltophilia acquisition of resistance. The expression of some of these genes is triggered by specific signals or stressors, which can lead to transient phenotypic resistance.Expert opinion: Treatment of S. maltophilia infections is difficult because this organism presents low susceptibility to antibiotics. Besides, it can acquire resistance to antimicrobials currently in use. Particularly problematic is the selection of mutants overexpressing efflux pumps since they present a multidrug resistance phenotype. The use of novel antimicrobials alone or in combination, together with the development of efflux pumps' inhibitors may help in fighting S. maltophilia infections. | 2020 | 32052662 |
| 9801 | 12 | 0.9998 | Problems and changing patterns of resistance with gram-negative bacteria. Throughout the antibiotic era, the emergence of drug-resistant bacteria has paralleled the development of new antimicrobial agents. As a result of selection pressures and invasive techniques that prolong the lives of seriously ill hospital patients, gram-negative bacilli have become the dominant causes of nosocomial infection. These microorganisms produce a diversity of antibiotic-inactivating enzymes. Moreover, the cell envelope of gram-negative bacteria provides a series of barriers that keep antibiotics from reaching their targets. Resistance factors can be transmitted among bacteria of different genera and species, thus conferring multidrug resistance. These problems continue to challenge scientists to better understand resistance mechanisms and to develop new compounds to circumvent them. | 1985 | 3909311 |
| 9776 | 13 | 0.9998 | Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Polymyxins are polycationic antimicrobial peptides that are currently the last-resort antibiotics for the treatment of multidrug-resistant, Gram-negative bacterial infections. The reintroduction of polymyxins for antimicrobial therapy has been followed by an increase in reports of resistance among Gram-negative bacteria. Some bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, develop resistance to polymyxins in a process referred to as acquired resistance, whereas other bacteria, such as Proteus spp., Serratia spp., and Burkholderia spp., are naturally resistant to these drugs. Reports of polymyxin resistance in clinical isolates have recently increased, including acquired and intrinsically resistant pathogens. This increase is considered a serious issue, prompting concern due to the low number of currently available effective antibiotics. This review summarizes current knowledge concerning the different strategies bacteria employ to resist the activities of polymyxins. Gram-negative bacteria employ several strategies to protect themselves from polymyxin antibiotics (polymyxin B and colistin), including a variety of lipopolysaccharide (LPS) modifications, such as modifications of lipid A with phosphoethanolamine and 4-amino-4-deoxy-L-arabinose, in addition to the use of efflux pumps, the formation of capsules and overexpression of the outer membrane protein OprH, which are all effectively regulated at the molecular level. The increased understanding of these mechanisms is extremely vital and timely to facilitate studies of antimicrobial peptides and find new potential drugs targeting clinically relevant Gram-negative bacteria. | 2014 | 25505462 |
| 4429 | 14 | 0.9998 | General mechanisms of resistance to antibiotics. Resistance to antimicrobial agents may result from intrinsic properties of organisms, through mutation and through plasmid- and transposon-specified genes. beta-Lactam resistance is most frequently associated with one or more chromosomal- or plasmid-specified beta-lactamases. Recently, mutations modifying penicillin-binding proteins have been detected with increased frequency as a cause of beta-lactam resistance. Mixed mechanisms, reduced permeability and tolerance are other causes of resistance. Aminoglycoside resistance always involves some modification of drug uptake, most often due to a variety of enzymes modifying these compounds. Reduced uptake is a primary cause of resistance in anaerobic bacteria and bacteria growing anaerobically, some strains of Pseudomonas aeruginosa, and mutants that arise during antimicrobial therapy and are defective in energy-generation systems. Resistance to other antimicrobial agents is presented in tabular form. | 1988 | 3062000 |
| 9799 | 15 | 0.9998 | Microbiology and drug resistance mechanisms of fully resistant pathogens. The acquisition of vancomycin resistance by Gram-positive bacteria and carbapenem resistance by Gram-negative bacteria has rendered some hospital-acquired pathogens impossible to treat. The resistance mechanisms employed are sophisticated and very difficult to overcome. Unless alternative treatment regimes are initiated soon, our inability to treat totally resistant bacteria will halt other developments in medicine. In the community, Gram-positive bacteria responsible for pneumonia could become totally resistant leading to increased mortality from this common infection, which would have a more immediate impact on our current lifestyles. | 2004 | 15451497 |
| 4316 | 16 | 0.9998 | Why do antimicrobial agents become ineffectual? Antibiotic resistance has evolved over the past 50 years from a merely microbiological curiosity to a serious medical problem in hospitals all over the world. Resistance has been reported in almost all species of gram-positive and -negative bacteria to various classes of antibiotics including recently developed ones. Bacteria acquire resistance by reducing permeability and intracellular accumulation, by alteration of targets of antibiotic action, and by enzymatic modification of antibiotics. Inappropriate use of an antibiotic selects resistant strains much more frequently. Once resistant bacteria has emerged, the resistance can be transferred to other bacteria by various mechanisms, resulting in multiresistant strains. MRSA is one of the typical multiresistant nosocomial pathogens. A study of the PFGE pattern of endonuclease-digested chromosomal DNA showed that MRSA of a few clones were disseminated among newborns in the NICU of a Japanese hospital. In this regard, it is important to choose appropriate antibiotics and then after some time, to change to other classes to reduce the selection of resistant strains. Since the development of epoch-making new antibiotics is not expected in the near future, it has become very important to use existing antibiotics prudently based on mechanisms of antibiotic action and bacterial resistance. Control of nosocomial infection is also very important to reduce further spread of resistant bacteria. | 1998 | 10097676 |
| 4444 | 17 | 0.9998 | Mechanisms of resistance to fluoroquinolones. Fluoroquinolones have some of the properties of an 'ideal' anti-microbial agent. Because of their potent broad spectrum activity and absence of transferable mechanism of resistance or inactivating enzymes, it was hoped that clinical resistance to this useful group of drugs would not occur. However, over the years, due to intense selective pressure and relative lack of potency of the available quinolones against some strains, bacteria have evolved at least two mechanisms of resistance: (i) alteration of molecular targets, and (ii) reduction of drug accumulation. DNA gyrase and topoisomerase IV are the two molecular targets of fluoroquinolones. Mutations in specified regions (quinolone resistance-determining region) in genes coding for the gyrase and/or topoisomerase leads to clinical resistance. An efflux pump effective in pumping out hydrophilic quinolones has been described. Newer fluoroquinolones which recognize both molecular targets and have improved pharmacokinetic properties offer hope of higher potency, thereby reducing the probability of development of resistance. | 1999 | 10573971 |
| 8849 | 18 | 0.9998 | Attenuating the Selection of Vancomycin Resistance Among Enterococci through the Development of Peptide-Based Vancomycin Antagonists. The emergence and spread of multidrug resistant (MDR) pathogens with acquired resistance to almost all available antimicrobial agents has severely threatened the international healthcare community over the last two decades. The last resort antibiotic vancomycin is critical for treatment of several of these pathogens; howeverc vancomycin resistance is spreading due to the undesired accumulation of IV vancomycin in the colon post-treatment. This accumulation exerts selective pressure upon members of the colonic microflora, including Enterococci, which possess vancomycin resistance genes. To ensure the continual effectiveness of vancomycin in the clinical setting by preventing the spread of antibiotic resistance, it is crucial to develop strategies that reduce selective pressure on the colonic microflora while allowing vancomycin to maintain its desired activity at the site of infection. Herein we report that modification of the native l-Lys-d-Ala-d-Ala vancomycin binding site can be used to produce peptides with the ability to competitively bind vancomycin, reducing its activity against susceptible Enterococci. Moreover, several modifications to the N-termini of the native tripeptide have produced compounds with enhanced vancomycin binding activity, including several analogs that were designed to covalently bind vancomycin, thereby acting as suicide inhibitors. Finally, in a mixed culture of susceptible and resistant bacteria, a single lead compound was found to protect high ratios of susceptible bacteria from vancomycin over the course of a week-long period, preventing the selection for vancomycin-resistant Enterococci. These findings demonstrate the ability of these peptides as potential therapeutic adjuvants for counteracting the undesired accumulation of colonic vancomycin, allowing for protection of the colonic microflora. | 2020 | 32946213 |
| 9100 | 19 | 0.9998 | Unlocking the bacterial membrane as a therapeutic target for next-generation antimicrobial amphiphiles. Gram-positive bacteria like Enterococcus faecium and Staphylococcus aureus, and Gram-negative bacteria like Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter Spp. are responsible for most of fatal bacterial infections. Bacteria present a handful of targets like ribosome, RNA polymerase, cell wall biosynthesis, and dihydrofolate reductase. Antibiotics targeting the protein synthesis like aminoglycosides and tetracyclines, inhibitors of RNA/DNA synthesis like fluoroquinolones, inhibitors of cell wall biosynthesis like glycopeptides and β-lactams, and membrane-targeting polymyxins and lipopeptides have shown very good success in combating the bacterial infections. Ability of the bacteria to develop drug resistance is a serious public health challenge as bacteria can develop antimicrobial resistance against newly introduced antibiotics that enhances the challenge for antibiotic drug discovery. Therefore, bacterial membranes present a suitable therapeutic target for development of antimicrobials as bacteria can find it difficult to develop resistance against membrane-targeting antimicrobials. In this review, we present the recent advances in engineering of membrane-targeting antimicrobial amphiphiles that can be effective alternatives to existing antibiotics in combating bacterial infections. | 2021 | 34325929 |