# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 207 | 0 | 1.0000 | Synthesis of an amphiphilic vancomycin aglycone derivative inspired by polymyxins: overcoming glycopeptide resistance in Gram-positive and Gram-negative bacteria in synergy with teicoplanin in vitro. Gram-negative bacteria possess intrinsic resistance to glycopeptide antibiotics so these important antibacterial medications are only suitable for the treatment of Gram-positive bacterial infections. At the same time, polymyxins are peptide antibiotics, structurally related to glycopeptides, with remarkable activity against Gram-negative bacteria. With the aim of breaking the intrinsic resistance of Gram-negative bacteria against glycopeptides, a polycationic vancomycin aglycone derivative carrying an n-decanoyl side chain and five aminoethyl groups, which resembles the structure of polymyxins, was prepared. Although the compound by itself was not active against the Gram-negative bacteria tested, it synergized with teicoplanin against Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii, and it was able to potentiate vancomycin against these Gram-negative strains. Moreover, it proved to be active against vancomycin- and teicoplanin-resistant Gram-positive bacteria. | 2022 | 36463278 |
| 4504 | 1 | 0.9996 | Resistance of enterococci to aminoglycosides and glycopeptides. High-level resistance to aminoglycosides in enterococci often is mediated by aminoglycoside-modifying enzymes, and the corresponding genes generally are located on self-transferable plasmids. These enzymes are similar to those in staphylococci but differ from the modifying enzymes of gram-negative bacteria. Three classes of enzymes are distinguished, depending upon the reaction catalyzed. All but amikacin and netilmicin confer high-level resistance to the antibiotics that are modified in vitro. However, the synergistic activity of these last two antibiotics in combination with beta-lactam agents can be suppressed, as has always been found in relation to high-level resistance to the aminoglycosides. Acquisition of glycopeptide resistance by enterococci recently was reported. Strains of two phenotypes have been distinguished: those that are resistant to high levels of vancomycin and teicoplanin and those that are inducibly resistant to low levels of vancomycin and susceptible to teicoplanin. In strains of Enterococcus faecium highly resistant to glycopeptides, we have characterized plasmids ranging from 34 to 40 kilobases that are often self-transferable to other gram-positive organisms. The resistance gene vanA has been cloned, and its nucleotide sequence has been determined. Hybridization experiments showed that this resistance determinant is present in all of our enterococcal strains that are highly resistant to glycopeptides. The vanA gene is part of a cluster of plasmid genes responsible for synthesis of peptidoglycan precursors containing a depsipeptide instead of the usual D-alanyl-D-alanine terminus. Reduced affinity of glycopeptides to these precursors confers resistance to the antibiotics. | 1992 | 1520800 |
| 206 | 2 | 0.9996 | Review of preclinical studies with ofloxacin. Most Enterobacteriaceae, enteropathogens, and fastidious gram-negative bacteria are highly susceptible to ofloxacin, a new tricyclic fluoroquinolone. Aerobic gram-negative bacilli and gram-positive bacteria are generally not as susceptible to ofloxacin. Obligate anaerobes are generally resistant to ofloxacin, while many mycobacteria, chlamydiae, legionellae, and mycoplasmas are susceptible. Ofloxacin is generally less active than ciprofloxacin against gram-negative bacteria, is similarly active against gram-positive bacteria, mycobacteria, legionellae, and mycoplasmas, and is more active against chlamydiae. However, numerous animal studies have shown these two fluoroquinolones to be similar. Ofloxacin inhibits DNA synthesis, is rapidly bactericidal, and is 1,000-2,400 times more potent against prokaryotic gyrase than against eukaryotic gyrase. The bactericidal effect of ofloxacin is not completely neutralized by inhibitors of protein or RNA synthesis. Resistance to ofloxacin arises from mutations within chromosomal genes involved with DNA gyrase and drug permeation. Selection of resistant mutants by ofloxacin is not as frequent as that seen with nalidixic acid. However, due to the cross-resistance between ofloxacin and other fluoroquinolones, all of these drugs should be used judiciously to preserve their clinical utility. | 1992 | 1554842 |
| 9777 | 3 | 0.9995 | Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Infections caused by multidrug-resistant (MDR) Gram-negative bacteria represent a major global health problem. Polymyxin antibiotics such as colistin have resurfaced as effective last-resort antimicrobials for use against MDR Gram-negative pathogens, including Acinetobacter baumannii. Here we show that A. baumannii can rapidly develop resistance to polymyxin antibiotics by complete loss of the initial binding target, the lipid A component of lipopolysaccharide (LPS), which has long been considered to be essential for the viability of Gram-negative bacteria. We characterized 13 independent colistin-resistant derivatives of A. baumannii type strain ATCC 19606 and showed that all contained mutations within one of the first three genes of the lipid A biosynthesis pathway: lpxA, lpxC, and lpxD. All of these mutations resulted in the complete loss of LPS production. Furthermore, we showed that loss of LPS occurs in a colistin-resistant clinical isolate of A. baumannii. This is the first report of a spontaneously occurring, lipopolysaccharide-deficient, Gram-negative bacterium. | 2010 | 20855724 |
| 4434 | 4 | 0.9995 | 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 |
| 9783 | 5 | 0.9995 | Synergism between Rifampicin and Cationic Polyurethanes Overcomes Intrinsic Resistance of Escherichia coli. Antibiotic-resistant Gram-negative bacteria are emergent pathogens, causing millions of infections worldwide. While there are several classes of antibiotics that are effective against Gram-positive bacteria, the outer membrane (OM) of Gram-negative bacteria excludes high-molecular-weight hydrophobic antibiotics, making these species intrinsically resistant to several classes of antibiotics, including polyketides, aminocoumarins, and macrolides. The overuse of antibiotics such as β-lactams has also promoted the spread of resistance genes throughout Gram-negative bacteria, including the production of extended spectrum β-lactamases (ESBLs). The combination of innate and acquired resistance makes it extremely challenging to identify antibiotics that are effective against Gram-negative bacteria. In this study, we have demonstrated the synergistic effect of outer membrane-permeable cationic polyurethanes with rifampicin, a polyketide that would otherwise be excluded by the OM, on different strains of E. coli, including a clinically isolated uropathogenic multidrug-resistant (MDR) E. coli. Rifampicin combined with a low-dose treatment of a cationic polyurethane reduced the MIC in E. coli of rifampicin by up to 64-fold. The compositions of cationic polyurethanes were designed to have low hemolysis and low cell cytotoxicity while maintaining high antibacterial activity. Our results demonstrate the potential to rescue the large number of available OM-excluded antibiotics to target normally resistant Gram-negative bacteria via synergistic action with these cationic polyurethanes, acting as a novel antibiotic adjuvant class. | 2021 | 34085824 |
| 4481 | 6 | 0.9995 | New findings in beta-lactam and metronidazole resistant Bacteroides fragilis group. Beta-lactam antibiotics and 5-nitroimidazoles have been extensively used against anaerobic bacteria. However, antibiotic resistance is increasingly common among anaerobic Gram-negative bacilli. The classical mechanisms of resistance to beta-lactams are, (1) production of beta-lactamases; (2) alteration of penicillin-binding proteins (PBPs); and (3) changes in outer membrane permeability to beta-lactams. The 5-nitroimidazole molecule is a prodrug whose activation depends upon reduction of the nitro group in the absence of oxygen. Decreased uptake and altered reduction are believed to be responsible for metronidazole resistance. Five nim genes (A, B, C, D and E) have been identified in Bacteroides fragilis group spp. that confer resistance to 5-nitroimidazole antibiotics. Knowledge of the status and the mechanisms of resistance is critical for both the selection of antimicrobial therapy and the design of new antimicrobial agents. The purpose of this article is to review the mechanisms for and the prevalence of beta-lactam and metronidazole resistance in strains belonging to the B. fragilis group. | 2002 | 12007843 |
| 9779 | 7 | 0.9995 | Mechanisms of Polymyxin Resistance. Polymyxin antibiotics are increasingly being used as last-line therapeutic options against a number of multidrug resistant bacteria. These antibiotics show strong bactericidal activity against a range of Gram-negative bacteria, but with the increased use of these antibiotics resistant strains are emerging at an alarming rate. Furthermore, some Gram-negative species, such as Neisseria meningitidis, Proteus mirabilis and Burkholderia spp., are intrinsically resistant to the action of polymyxins. Most identified polymyxin resistance mechanisms in Gram-negative bacteria involve changes to the lipopolysaccharide (LPS) structure, as polymyxins initially interact with the negatively charged lipid A component of LPS. The controlled addition of positively charged residues such as 4-amino-(L)-arabinose, phosphoethanolamine and/or galactosamine to LPS results in a reduced negative charge on the bacterial surface and therefore reduced interaction between the polymyxin and the LPS. Polymyxin resistant species produce LPS that intrinsically contains one or more of these additions. While the genes necessary for most of these additions are chromosomally encoded, plasmid-borne phosphoethanolamine transferases (mcr-1 to mcr-8) have recently been identified and these plasmids threaten to increase the rate of dissemination of clinically relevant colistin resistance. Uniquely, Acinetobacter baumannii can also become highly resistant to polymyxins via spontaneous mutations in the lipid A biosynthesis genes lpxA, lpxC or lpxD such that they produce no LPS or lipid A. A range of other non-LPS-dependent polymyxin resistance mechanisms has also been identified in bacteria, but these generally result in only low levels of resistance. These include increased anionic capsular polysaccharide production in Klebsiella pneumoniae, expression of efflux systems such as MtrCDE in N. meningitidis, and altered expression of outer membrane proteins in a small number of species. | 2019 | 31364071 |
| 4435 | 8 | 0.9994 | Bacterial resistance to the cyclic glycopeptides. Cyclic-glycopeptide antibiotics, such as vancomycin and teicoplanin, have been almost uniformly active against pathogenic Gram-positive bacteria since their discovery in the 1950s. Resistance is now emerging among enterococci and staphylococci by acquisition of novel genes or by mutation, respectively. The mechanism of resistance for enterococci appears to be synthesis of an altered cell-wall precursor with lower affinity for the antibiotics. | 1994 | 7850206 |
| 4429 | 9 | 0.9994 | 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 |
| 9778 | 10 | 0.9994 | Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria. Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of Escherichia coli. We recognized common structural elements between this hit and a previously published inhibitor, also with activity against efflux-deficient bacteria. With the help of X-ray structures, this information was used to design inhibitors with activity on efflux-proficient, wild-type strains. Optimization of properties such as solubility, metabolic stability and serum protein binding resulted in compounds having potent in vivo efficacy against bloodstream infections caused by the critical Gram-negative pathogens E. coli and Klebsiella pneumoniae. Other favorable properties of the series include a lack of pre-existing resistance in clinical isolates, and no loss of activity against strains expressing extended-spectrum-β-lactamase, metallo-β-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance. | 2024 | 38579010 |
| 6250 | 11 | 0.9994 | High prevalence of heteroresistance in Staphylococcus aureus is caused by a multitude of mutations in core genes. Heteroresistance (HR) is an enigmatic phenotype where, in a main population of susceptible cells, small subpopulations of resistant cells exist. This is a cause for concern, as this small subpopulation is difficult to detect by standard antibiotic susceptibility tests, and upon antibiotic exposure the resistant subpopulation may increase in frequency and potentially lead to treatment complications or failure. Here, we determined the prevalence and mechanisms of HR for 40 clinical Staphylococcus aureus isolates, against 6 clinically important antibiotics: daptomycin, gentamicin, linezolid, oxacillin, teicoplanin, and vancomycin. High frequencies of HR were observed for gentamicin (69.2%), oxacillin (27%), daptomycin (25.6%), and teicoplanin (15.4%) while none of the isolates showed HR toward linezolid or vancomycin. Point mutations in various chromosomal core genes, including those involved in membrane and peptidoglycan/teichoic acid biosynthesis and transport, tRNA charging, menaquinone and chorismite biosynthesis and cyclic-di-AMP biosynthesis, were the mechanisms responsible for generating the resistant subpopulations. This finding is in contrast to gram-negative bacteria, where increased copy number of bona fide resistance genes via tandem gene amplification is the most prevalent mechanism. This difference can be explained by the observation that S. aureus has a low content of resistance genes and absence of the repeat sequences that allow tandem gene amplification of these genes as compared to gram-negative species. | 2024 | 38175839 |
| 9780 | 12 | 0.9994 | Colistin resistance in Escherichia coli confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic. Colistin is a polymyxin antibiotic of last resort for the treatment of infections caused by multi-drug-resistant Gram-negative bacteria. By targeting lipopolysaccharide (LPS), the antibiotic disrupts both the outer and cytoplasmic membranes, leading to bacterial death and lysis. Colistin resistance in Escherichia coli occurs via mutations in the chromosome or the acquisition of mobilized colistin-resistance (mcr) genes. Both these colistin-resistance mechanisms result in chemical modifications to the LPS, with positively charged moieties added at the cytoplasmic membrane before the LPS is transported to the outer membrane. We have previously shown that MCR-1-mediated LPS modification protects the cytoplasmic but not the outer membrane from damage caused by colistin, enabling bacterial survival. However, it remains unclear whether this observation extends to colistin resistance conferred by other mcr genes, or resistance due to chromosomal mutations. Using a panel of clinical E. coli that had acquired mcr -1, -1.5, -2, -3, -3.2 or -5, or had acquired polymyxin resistance independently of mcr genes, we found that almost all isolates were susceptible to colistin-mediated permeabilization of the outer, but not cytoplasmic, membrane. Furthermore, we showed that permeabilization of the outer membrane of colistin-resistant isolates by the polymyxin is in turn sufficient to sensitize bacteria to the antibiotic rifampicin, which normally cannot cross the LPS monolayer. These findings demonstrate that colistin resistance in these E. coli isolates is due to protection of the cytoplasmic but not outer membrane from colistin-mediated damage, regardless of the mechanism of resistance. | 2021 | 34723787 |
| 4419 | 13 | 0.9994 | Epidemiology of tetracycline-resistance determinants. Resistance to tetracycline is generally due either to energy-dependent efflux of tetracycline or to protection of the bacterial ribosomes from the action of tetracycline. The genes that encode this resistance are normally acquired via transferable plasmids and/or transposons. Tet determinants have been found in a wide range of Gram-positive and Gram-negative bacteria and have reduced the effectiveness of therapy with tetracycline. | 1994 | 7850200 |
| 4829 | 14 | 0.9994 | Diversity of the mechanisms of resistance to beta-lactam antibiotics. The sensitivity of a bacterium to beta-lactam antibiotics depends upon the interplay between 3 independent factors: the sensitivity of the essential penicillin-binding enzyme(s), the quantity and properties of the beta-lactamase(s) and the diffusion barrier that the outer-membrane of Gram-negative bacteria can represent. Those three factors can be modified by mutations or by the horizontal transfer of genes or portions of genes. | 1991 | 1961980 |
| 211 | 15 | 0.9994 | Preclinical pharmacology of GAR-936, a novel glycylcycline antibacterial agent. GAR-936 is an analog of minocycline, a semisynthetic derivative of tetracycline. It has broad-spectrum antibacterial activity in vitro and in vivo. The new class of tetracyclines to which GAR-936 belongs is named the glycylcyclines. Tetracyclines act by inhibiting protein translation in bacteria, presumably by binding to the 30S ribosomal subunit and blocking entry of amino-acyl transfer RNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. In general, tetracyclines are considered bacteriostatic and the critical therapeutic parameter is the area under the concentration-time curve. GAR-936 has bactericidal activity; at 4 times the minimum inhibitory concentration, a 2- to 3-log reduction in colony counts was seen against Streptococcus pneumoniae, Neisseria gonorrhoeae, Haemophilus influenzae, Escherichia coli, and Staphylococcus aureus. GAR-936 is active against the antibiotic-resistant gram-positive bacteria methicillin-resistant Staphylococcus aureus, penicillin-resistant S. pneumoniae, and vancomycin-resistant enterococci. It is most significant that GAR-936 and other glycylcyclines are active against bacterial strains carrying either or both of the two major forms of tetracycline resistance: efflux and ribosomal protection. Using isogenic panels of bacteria carrying various tetracycline-resistance determinants, a series of more than 300 analogs was tested for antibacterial activity, which allowed for structure-activity relationships to be determined. Results indicated that certain substituents at the 9 position of the tetracycline molecule restored activity against bacteria harboring genes encoding either or both efflux and ribosomal protection. A single chemical modification overcame the two molecularly distinct forms of resistance while maintaining activity against susceptible gram-positive, gram-negative, aerobic, and anaerobic bacteria. Although mutants can be generated that are less susceptible to previously studied glycylcyclines, only marginal differences in susceptibility to GAR-936 were noted. Therefore, whereas emergence of resistance to any widely administered antibiotic is a foregone conclusion, resistance to GAR-936 will not readily arise by trivial mutations in existing resistance genes. | 2000 | 11001329 |
| 4443 | 16 | 0.9994 | 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 |
| 9926 | 17 | 0.9994 | beta-Lactamases of gram-negative bacteria: new challenges for new drugs. The major emphasis in new drug design within the beta-lactam family has been on compounds less susceptible to hydrolysis by beta-lactamases and on combinations containing an enzyme-labile drug plus a beta-lactamase inhibitor. The introduction of such new compounds into clinical use has been followed by the discovery of novel mechanisms of resistance among gram-negative bacteria. These include the appearance of new enzymes, many of which are derivatives of older beta-lactamases. In addition, genes for certain broad-spectrum enzymes previously restricted to chromosomal sites have moved onto plasmids. There is now a greater appreciation of how alterations in enzyme expression--either alone or in concert with changes in drug permeation--can also lead to resistance. Clearly, recent events in the development of new beta-lactam agents have led to a new phase in the understanding of beta-lactam resistance. | 1992 | 1600011 |
| 9774 | 18 | 0.9994 | A naturally inspired antibiotic to target multidrug-resistant pathogens. Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections(1,2). The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin(3). Bacteria-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters. This structural diversity is, at least in part, expected to be a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here we propose that a solution to mcr-1-mediated resistance might have evolved among naturally occurring colistin congeners. Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes. These Gram-negative bacteria include extensively drug-resistant Acinetobacter baumannii and intrinsically colistin-resistant Neisseria gonorrhoeae, which, owing to a lack of effective treatment options, are considered among the highest level threat pathogens(4). In a mouse neutropenic infection model, a biphenyl analogue of macolacin proved to be effective against extensively drug-resistant A. baumannii with colistin-resistance, thus providing a naturally inspired and easily produced therapeutic lead for overcoming colistin-resistant pathogens. | 2022 | 34987225 |
| 9782 | 19 | 0.9994 | Homodimeric Tobramycin Adjuvant Repurposes Novobiocin as an Effective Antibacterial Agent against Gram-Negative Bacteria. Low permeability across the outer membrane is a major reason why most antibiotics are ineffective against Gram-negative bacteria. Agents that permeabilize the outer membrane are typically toxic at their effective concentrations. Here, we report the development of a broad-spectrum homodimeric tobramycin adjuvant that is nontoxic and more potent than the gold standard permeabilizing agent, polymyxin B nonapeptide. In pilot studies, the adjuvant confers potent bactericidal activity on novobiocin against Gram-negative bacteria, including carbapenem-resistant and colistin-resistant strains bearing plasmid-borne mcr-1 genes. Resistance development to the combination was significantly reduced, relative to novobiocin alone, and there was no induction of cross-resistance to other antibiotics, including the gyrase-acting fluoroquinolones. Tobramycin homodimer may allow the use of lower doses of novobiocin, overcoming its twin problem of efficacy and toxicity. | 2019 | 31557020 |