# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 4838 | 0 | 1.0000 | Cooperative resistance varies among β-lactamases in E. coli, with some enabling cross-protection and sustained extracellular activity. β-lactamases confer bacteria resistance to β-lactam antibiotics, and interestingly, this protective effect can extend to neighboring susceptible cells. However, knowledge of this cooperative resistance remains limited. Here, we investigated the underlying factors of cooperative resistance to assess commonalities and differences among the highly diverse group of β-lactamases. We first analyzed β-lactamase genes from 2637 Escherichia coli genomes, followed by experimental characterization of seven prevalent β-lactamase genes. Larger plasmids, particularly conjugative ones, commonly encoded β-lactamases. All seven genes had strong wildtype promoters, and plasmid-based expression rescued more susceptible bacteria than chromosomal expression. Cooperative resistance positively correlated with β-lactamase activity and minimal inhibitory concentrations. Cross-protection could be established between different β-lactamase producers, challenging the effectiveness of therapies combining β-lactams. Extracellular activity varied among β-lactamases and, when high, resulted in a legacy resistance effect in the environment. These findings advance our understanding of β-lactam resistance and highlight important implications for antibiotic treatment strategies. | 2025 | 40595357 |
| 9942 | 1 | 0.9998 | Exploring the Potential of CRISPR-Cas9 Under Challenging Conditions: Facing High-Copy Plasmids and Counteracting Beta-Lactam Resistance in Clinical Strains of Enterobacteriaceae. The antimicrobial resistance (AMR) crisis urgently requires countermeasures for reducing the dissemination of plasmid-borne resistance genes. Of particular concern are opportunistic pathogens of Enterobacteriaceae. One innovative approach is the CRISPR-Cas9 system which has recently been used for plasmid curing in defined strains of Escherichia coli. Here we exploited this system further under challenging conditions: by targeting the bla (TEM-) (1) AMR gene located on a high-copy plasmid (i.e., 100-300 copies/cell) and by directly tackling bla (TEM-) (1)-positive clinical isolates. Upon CRISPR-Cas9 insertion into a model strain of E. coli harboring bla (TEM-) (1) on the plasmid pSB1A2, the plasmid number and, accordingly, the bla (TEM-) (1) gene expression decreased but did not become extinct in a subpopulation of CRISPR-Cas9 treated bacteria. Sequence alterations in bla (TEM-) (1) were observed, likely resulting in a dysfunction of the gene product. As a consequence, a full reversal to an antibiotic sensitive phenotype was achieved, despite plasmid maintenance. In a clinical isolate of E. coli, plasmid clearance and simultaneous re-sensitization to five beta-lactams was possible. Reusability of antibiotics could be confirmed by rescuing larvae of Galleria mellonella infected with CRISPR-Cas9-treated E. coli, as opposed to infection with the unmodified clinical isolate. The drug sensitivity levels could also be increased in a clinical isolate of Enterobacter hormaechei and to a lesser extent in Klebsiella variicola, both of which harbored additional resistance genes affecting beta-lactams. The data show that targeting drug resistance genes is encouraging even when facing high-copy plasmids. In clinical isolates, the simultaneous interference with multiple genes mediating overlapping drug resistance might be the clue for successful phenotype reversal. | 2020 | 32425894 |
| 4906 | 2 | 0.9998 | Factors that affect transfer of the IncI1 β-lactam resistance plasmid pESBL-283 between E. coli strains. The spread of antibiotic resistant bacteria worldwide presents a major health threat to human health care that results in therapy failure and increasing costs. The transfer of resistance conferring plasmids by conjugation is a major route by which resistance genes disseminate at the intra- and interspecies level. High similarities between resistance genes identified in foodborne and hospital-acquired pathogens suggest transmission of resistance conferring and transferrable mobile elements through the food chain, either as part of intact strains, or through transfer of plasmids from foodborne to human strains. To study the factors that affect the rate of plasmid transfer, the transmission of an extended-spectrum β-lactamase (ESBL) plasmid from a foodborne Escherichia coli strain to the β-lactam sensitive E. coli MG1655 strain was documented as a function of simulated environmental factors. The foodborne E. coli isolate used as donor carried a CTX-M-1 harboring IncI1 plasmid that confers resistance to β-lactam antibiotics. Cell density, energy availability and growth rate were identified as factors that affect plasmid transfer efficiency. Transfer rates were highest in the absence of the antibiotic, with almost every acceptor cell picking up the plasmid. Raising the antibiotic concentrations above the minimum inhibitory concentration (MIC) resulted in reduced transfer rates, but also selected for the plasmid carrying donor and recombinant strains. Based on the mutational pattern of transconjugant cells, a common mechanism is proposed which compensates for fitness costs due to plasmid carriage by reducing other cell functions. Reducing potential fitness costs due to maintenance and expression of the plasmid could contribute to persistence of resistance genes in the environment even without antibiotic pressure. Taken together, the results identify factors that drive the spread and persistence of resistance conferring plasmids in natural isolates and shows how these can contribute to transmission of resistance genes through the food chain. | 2015 | 25830294 |
| 4840 | 3 | 0.9998 | Beta-lactam antibiotics and selection of resistance: speculation on the evolution of R-plasmids. In this paper we describe two genetic mechanisms which are responsible for the development of resistance to third-generation cephalosporins. One is a plasmid-mediated mechanism involving a mutation in the SHV-1-gene towards the production of the beta-lactamase SHV-2 which has increased affinity for these antibiotics. The other is chromosomally mediated and occurs at high frequency by mutation of inducible beta-lactamase-genes, leading to derepressed production of the enzyme. Together with other examples of resistance genes these two mechanisms lead us to a hypothesis about the evolution of beta-lactamase producing bacteria. | 1986 | 3542929 |
| 4839 | 4 | 0.9998 | beta-Lactamases: protein evolution in real time. The evolution and spread of bacteria resistant to beta-lactam antibiotics has progressed at an alarming rate. Bacteria may acquire resistance to a given drug by mutation of pre-existing genes or by the acquisition of new genes from other bacteria. One ongoing example of these mechanisms is the evolution of new variants of the TEM and SHV beta-lactamases with altered substrate specificity. | 1998 | 9746943 |
| 3821 | 5 | 0.9998 | Persistence of transferable extended-spectrum-β-lactamase resistance in the absence of antibiotic pressure. The treatment of infections caused by antibiotic-resistant bacteria is one of the great challenges faced by clinicians in the 21st century. Antibiotic resistance genes are often transferred between bacteria by mobile genetic vectors called plasmids. It is commonly believed that removal of antibiotic pressure will reduce the numbers of antibiotic-resistant bacteria due to the perception that carriage of resistance imposes a fitness cost on the bacterium. This study investigated the ability of the plasmid pCT, a globally distributed plasmid that carries an extended-spectrum-β-lactamase (ESBL) resistance gene (bla(CTX-M-14)), to persist and disseminate in the absence of antibiotic pressure. We investigated key attributes in plasmid success, including conjugation frequencies, bacterial-host growth rates, ability to cause infection, and impact on the fitness of host strains. We also determined the contribution of the bla(CTX-M-14) gene itself to the biology of the plasmid and host bacterium. Carriage of pCT was found to impose no detectable fitness cost on various bacterial hosts. An absence of antibiotic pressure and inactivation of the antibiotic resistance gene also had no effect on plasmid persistence, conjugation frequency, or bacterial-host biology. In conclusion, plasmids such as pCT have evolved to impose little impact on host strains. Therefore, the persistence of antibiotic resistance genes and their vectors is to be expected in the absence of antibiotic selective pressure regardless of antibiotic stewardship. Other means to reduce plasmid stability are needed to prevent the persistence of these vectors and the antibiotic resistance genes they carry. | 2012 | 22710119 |
| 4847 | 6 | 0.9998 | Escherichia coli β-Lactamases: What Really Matters. Escherichia coli strains belonging to diverse pathotypes have increasingly been recognized as a major public health concern. The β-lactam antibiotics have been used successfully to treat infections caused by pathogenic E. coli. However, currently, the utility of β-lactams is being challenged severely by a large number of hydrolytic enzymes - the β-lactamases expressed by bacteria. The menace is further compounded by the highly flexible genome of E. coli, and propensity of resistance dissemination through horizontal gene transfer and clonal spread. Successful management of infections caused by such resistant strains requires an understanding of the diversity of β-lactamases, their unambiguous detection, and molecular mechanisms underlying their expression and spread with regard to the most relevant information about individual bacterial species. Thus, this review comprises first such effort in this direction for E. coli, a bacterial species known to be associated with production of diverse classes of β-lactamases. The review also highlights the role of commensal E. coli as a potential but under-estimated reservoir of β-lactamases-encoding genes. | 2016 | 27065978 |
| 4845 | 7 | 0.9998 | The changing epidemiology of resistance. Antibiotic resistance is now a linked global problem. Dispersion of successful clones of multidrug resistant (MDR) bacteria is common, often via the movement of people. Local evolution of MDR bacteria is also important under the pressure of excessive antibiotic use, with horizontal gene transfer providing the means by which genes such as bla(CTX-M) spread amongst different bacterial species and strains. Beta-lactamase production is a common resistance mechanism in Gram-negative bacteria, and the rapid dissemination of novel genes reflects their evolution under the selective pressure of antibiotic usage. Many Enterobacteriaceae now carry broad-spectrum beta-lactamases such as CTX-M, with particular genotypes associated with different geographical regions. The spread of these enzymes has compromised the clinical utility of a number of beta-lactam classes and with the spread of genes such as bla(KPC), carbapenems may be increasingly compromised in the future. High-level fluoroquinolone resistance (mainly caused by gyrA mutations) has also been shown to be associated with CTX-M and CMY-type enzymes, commonly due to co-carriage on conjugative plasmids of the gene for the aminoglycoside-inactivating enzyme AAC-6(1)-Ib-cr and qnr genes (which confer low-level resistance), allowing the easy selection of gyrA mutants in the host strain. Resistance in Gram-positive bacteria is also widely distributed and increasing, with the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) blurring the distinction between hospital and community strains. Antibiotic use and environmental factors all have a role in the emergence and spread of resistance. This article reviews some of the new mechanisms and recent trends in the global spread of MDR bacteria. | 2009 | 19675017 |
| 4843 | 8 | 0.9998 | The Efficacy of Isolated Bacteriophages from Pig Farms against ESBL/AmpC-Producing Escherichia coli from Pig and Turkey Farms. Extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases are plasmid (but also chromosomally) encoded enzymes found in Enterobacteriaceae, determining resistance to a variety of important antibiotics including penicillins, cephalosporins, and monobactams. In recent decades, the prevalence of ESBL/AmpC-producing bacteria has increased rapidly across the world. Here, we evaluate the potential use of bacteriophages in terms of a reduction of antibiotic-resistant bacteria in healthy animals. The aim of our studies was to isolate bacteriophages capable of destroying ESBL/AmpC-producing Escherichia coli isolated from livestock habitats. The efficacy of isolated phages against ESBL/AmpC E. coli strains varies, but creation of a phage cocktail with broad activity spectrum is possible. This may indicate that the role of phages may not be limited to phage therapy, but bacterial viruses may also be applied against spread of bacteria with antibiotic resistance genes in the environment. We also addressed the hypothesis, that phages, effective for therapeutic purposes may be isolated from distant places and even from different environments other than the actual location of the targeted bacteria. This may be beneficial for practical purposes, as the construction of effective phage preparations does not require access to disease outbreaks. | 2017 | 28405193 |
| 4910 | 9 | 0.9998 | Excreted Antibiotics May Be Key to Emergence of Increasingly Efficient Antibiotic Resistance in Food Animal Production. At a time when antibiotic resistance is seemingly ubiquitous worldwide, understanding the mechanisms responsible for successful emergence of new resistance genes may provide insights into the persistence and pathways of dissemination for antibiotic-resistant organisms in general. For example, Escherichia coli strains harboring a class A β-lactamase-encoding gene (bla(CTX-M-15)) appear to be displacing strains that harbor a class C β-lactamase gene (bla(CMY-2)) in Washington State dairy cattle. We cloned these genes with native promoters into low-copy-number plasmids that were then transformed into isogenic strains of E. coli, and growth curves were generated for two commonly administered antibiotics (ampicillin and ceftiofur). Both strains met the definition of resistance for ampicillin (≥32 μg/mL) and ceftiofur (≥16 μg/mL). Growth of the CMY-2-producing strain was compromised at 1,000 μg/mL ampicillin, whereas the CTX-M-15-producing strain was not inhibited in the presence of 3,000 μg/mL ampicillin or with most concentrations of ceftiofur, although there were mixed outcomes with ceftiofur metabolites. Consequently, in the absence of competing genes, E. coli harboring either gene would experience a selective advantage if exposed to these antibiotics. Successful emergence of CTX-M-15-producing strains where CMY-2-producing strains are already established, however, requires high concentrations of antibiotics that can only be found in the urine of treated animals (e.g., >2,000 μg/mL for ampicillin, based on literature). This ex vivo selection pressure may be important for the emergence of new and more efficient antibiotic resistance genes and likely for persistence of antibiotic-resistant bacteria in food animal populations. IMPORTANCE We studied the relative fitness benefits of a cephalosporin resistance enzyme (CTX-M-15) that is displacing a similar enzyme (CMY-2), which is extant in E. coli from dairy cattle in Washington State. In vitro experiments demonstrated that CTX-M-15 provides a significant fitness advantage, but only in the presence of very high concentrations of antibiotic that are only found when the antibiotic ampicillin, and to a lesser extent ceftiofur, is excreted in urine from treated animals. As such, the increasing prevalence of bacteria with bla(CTX-M-15) is likely occurring ex vivo. Interventions should focus on controlling waste from treated animals and, when possible, selecting antibiotics that are less likely to impact the proximal environment of treated animals. | 2022 | 35867586 |
| 4844 | 10 | 0.9998 | Genetic basis of molecular mechanisms in β-lactam resistant gram-negative bacteria. Antibiotic-resistant bacteria are considered one of the major global threats to human and animal health. The most harmful among the resistant bacteria are β-lactamase producing Gram-negative species (β-lactamases). β-lactamases constitute a paradigm shift in the evolution of antibiotic resistance. Therefore, it is imperative to present a comprehensive review of the mechanisms responsible for developing antimicrobial resistance. Resistance due to β-lactamases develops through a variety of mechanisms, and the number of resistant genes are involved that can be transferred between bacteria, mostly via plasmids. Over time, these new molecular-based resistance mechanisms have been progressively disclosed. The present review article provides information on the recent findings regarding the molecular mechanisms of resistance to β-lactams in Gram-negative bacteria, including CTX-M-type ESBLs with methylase activity, plasmids harbouring phages with β-lactam resistance genes, the co-presence of β-lactam resistant genes of unique combinations and the presence of β-lactam and non-β-lactam antibiotic-resistant genes in the same bacteria. Keeping in view, the molecular level resistance development, multifactorial and coordinated measures may be taken to counter the challenge of rapidly increasing β-lactam resistance. | 2021 | 34119627 |
| 4671 | 11 | 0.9998 | Detection by metagenomic functional analysis and improvement by experimental evolution of β-lactams resistance genes present in oil contaminated soils. The spread of antibiotic resistance genes has become a global health concern identified by the World Health Organization as one of the greatest threats to health. Many of antimicrobial resistance determinants found in bacterial pathogens originate from environmental bacteria, so identifying the genes that confer resistance to antibiotics in different habitats is mandatory to better understand resistance mechanisms. Soil is one of the most diverse environments considered reservoir of antimicrobial resistance genes. The aim of this work is to study the presence of genes that provide resistance to antibiotics used in clinical settings in two oil contaminated soils by metagenomic functional analysis. Using fosmid vectors that efficiently transcribe metagenomic DNA, we have selected 12 fosmids coding for two class A β-lactamases, two subclass B1 and two subclass B3 metallo-β-lactamases, one class D β-lactamase and three efflux pumps that confer resistance to cefexime, ceftriaxone, meropenem and/or imipenem. In some of them, detection of the resistance required heterologous expression from the fosmid promoter. Although initially, these environmental genes only provide resistance to low concentrations of antibiotics, we have obtained, by experimental evolution, fosmid derivatives containing β-lactamase ORFs with a single base substitution, which substantially increase their β-lactamase activity and resistance level. None of the mutations affect β-lactamase coding sequences and are all located upstream of them. These results demonstrate the presence of enzymes that confer resistance to relevant β-lactams in these soils and their capacity to rapidly adapt to provide higher resistance levels. | 2022 | 35768448 |
| 4569 | 12 | 0.9998 | Effect of oxygen on antimicrobial resistance genes from a one health perspective. Bacteria must face and adapt to a variety of physicochemical conditions in the environment and during infection. A key condition is the concentration of dissolved oxygen, proportional to the partial pressure of oxygen (PO(2)), which is extremely variable among environmental biogeographical areas and also compartments of the human and animal body. Here, we sought to understand if the phenotype of resistance determinants commonly found in Enterobacterales can be influenced by oxygen pressure. To do so, we have compared the MIC in aerobic and anaerobic conditions of isogenic Escherichia coli strains containing 136 different resistance genes against 8 antibiotic families. Our results show a complex landscape of changes in the performance of resistance genes in anaerobiosis. Certain changes are especially relevant for their intensity and the importance of the antibiotic family, like the large decreases in resistance observed against ertapenem and fosfomycin among bla(VIM) β-lactamases and certain fos genes, respectively; however, the bla(OXA-48) β-lactamase from the clinically relevant pOXA-48 plasmid conferred 4-fold higher ertapenem resistance in anaerobiosis. Strong changes in resistance patterns in anaerobiosis were also conserved in Klebsiella pneumoniae. Our results suggest that anaerobiosis is a relevant aspect that can affect the action and selective power of antibiotics for specific AMRs in different environments. | 2025 | 40286623 |
| 4846 | 13 | 0.9998 | Mobile fosfomycin resistance genes in Enterobacteriaceae-An increasing threat. Antimicrobial resistance is one of the major threats to the health and welfare of both humans and animals. The shortage of new antimicrobial agents has led to the re-evaluation of old antibiotics such as fosfomycin as a potential regimen for treating multidrug-resistant bacteria especially extended-spectrum-beta-lactamase- and carbapenemase-producing Enterobacteriaceae. Fosfomycin is a broad-spectrum bactericidal antibiotic that inhibits the initial step of the cell wall biosynthesis. Fosfomycin resistance can occur due to mutation in the drug uptake system or by the acquisition of fosfomycin-modifying enzymes. In this review, we focus on mobile fosfomycin-resistant genes encoding glutathione-S-transferase which are mainly responsible for fosfomycin resistance in Enterobacteriaceae, that is, fosA and its subtypes, fosC2, and the recently described fosL1-L2. We summarized the proposed origins of the different resistance determinants and highlighted the different plasmid types which are attributed to the dissemination of fosfomycin-modifying enzymes. Thereby, IncF and IncN plasmids play a predominant role. The detection of mobile fosfomycin-resistant genes in Enterobacteriaceae has increased in recent years. Similar to the situation in (East) Asia, the most frequently detected fosfomycin-resistant gene in Europe is fosA3. Mobile fosfomycin-resistant genes have been detected in isolates of human, animal, food, and environmental origin which leads to a growing concern regarding the risk of spread of such bacteria, especially Escherichia coli and Salmonella, at the human-animal-environment interface. | 2020 | 33128341 |
| 5695 | 14 | 0.9998 | Competition assays between ESBL-producing E. coli and K. pneumoniae isolates collected from Lebanese elderly: An additional cost on fitness. The dissemination of Multi Drug Resistant Organisms (MDROs) is one of the major public health problems addressed nowadays. High fecal carriage rates of MDR Enterobacteriaceae were reported from Lebanese nursing homes. Studies have shown that the acquisition of resistance genes by bacteria might confer a fitness cost detected as a decrease in the frequency of these bacteria as compared to sensitive isolates. In this study, the competitive growth of MDR Enterobacteriaceae isolated from elderly is assessed. Sensitive and ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates were identified. Inter-species in-vitro competition assays were conducted in different combinations. ESBL-producing K. pneumoniae presented a fitness cost when competing against sensitive E. coli. On the other hand, resistant E. coli only showed a fitness cost when growing in presence of two sensitive K. pneumoniae isolates. These results suggest that ESBL-production genes in E. coli and K. pneumoniae may confer a fitness cost that leads to the decrease in frequency of these bacteria in interspecies competitions. Culturing bacteria in a medium with more diverse isolates can provide better insights into bacterial competition and resistance dynamics, which can be exploited in the search for alternative therapeutic approaches towards the colonization of resistant bacteria. | 2018 | 28988774 |
| 6267 | 15 | 0.9998 | Beta-lactamase dependent and independent evolutionary paths to high-level ampicillin resistance. The incidence of beta-lactam resistance among clinical isolates is a major health concern. A key method to study the emergence of antibiotic resistance is adaptive laboratory evolution. However, in the case of the beta-lactam ampicillin, bacteria evolved in laboratory settings do not recapitulate clinical-like resistance levels, hindering efforts to identify major evolutionary paths and their dependency on genetic background. Here, we used the Microbial Evolution and Growth Arena (MEGA) plate to select ampicillin-resistant Escherichia coli mutants with varying degrees of resistance. Whole-genome sequencing of resistant isolates revealed that ampicillin resistance was acquired via a combination of single-point mutations and amplification of the gene encoding beta-lactamase AmpC. However, blocking AmpC-mediated resistance revealed latent adaptive pathways: strains deleted for ampC were able to adapt through combinations of changes in genes involved in multidrug resistance encoding efflux pumps, transcriptional regulators, and porins. Our results reveal that combinations of distinct genetic mutations, accessible at large population sizes, can drive high-level resistance to ampicillin even independently of beta-lactamases. | 2024 | 38918379 |
| 9914 | 16 | 0.9998 | Identification of host genetic factors modulating β-lactam resistance in Escherichia coli harbouring plasmid-borne β-lactamase through transposon-sequencing. Since β-lactam antibiotics are widely used, emergence of bacteria with resistance to them poses a significant threat to society. In particular, acquisition of genes encoding β-lactamase, an enzyme that degrades β-lactam antibiotics, has been a major contributing factor in the emergence of bacteria that are resistant to β-lactam antibiotics. However, relatively few genetic targets for killing these resistant bacteria have been identified to date. Here, we used a systematic approach called transposon-sequencing (Tn-Seq), to screen the Escherichia coli genome for host genetic factors that, when mutated, affect resistance to ampicillin, one of the β-lactam antibiotics, in a strain carrying a plasmid that encodes β-lactamase. This approach enabled not just the isolation of genes previously known to affect β-lactam resistance, but the additional loci skp, gshA, phoPQ and ypfN. Individual mutations in these genes modestly but consistently affected antibiotic resistance. We have identified that these genes are not only implicated in β-lactam resistance by itself but also play a crucial role in conditions associated with the expression of β-lactamase. GshA and phoPQ appear to contribute to β-lactam resistance by regulating membrane integrity. Notably, the overexpression of the uncharacterized membrane-associated protein, ypfN, has been shown to significantly enhance β-lactam resistance. We applied the genes identified from the screening into Salmonella Typhimurium and Pseudomonas aeruginosa strains, both critical human pathogens with antibiotic resistance, and observed their significant impact on β-lactam resistance. Therefore, these genes can potentially be utilized as therapeutic targets to control the survival of β-lactamase-producing bacteria. | 2025 | 40231449 |
| 5059 | 17 | 0.9998 | Site-selective modifications by lipid A phosphoethanolamine transferases linked to colistin resistance and bacterial fitness. Genes encoding lipid A modifying phosphoethanolamine transferases (PETs) are genetically diverse and can confer resistance to colistin and antimicrobial peptides. To better understand the functional diversity of PETs, we characterized three canonical mobile colistin resistance (mcr) alleles (mcr-1, -3, -9), one intrinsic pet (eptA), and two mcr-like genes (petB, petC) in Escherichia coli. Using an isogenic expression system, we show that mcr-1 and mcr-3 confer similar phenotypes of decreased colistin susceptibility with low fitness costs. mcr-9, which is phylogenetically closely related to mcr-3, and eptA only provide fitness advantages in the presence of sub-inhibitory concentrations of colistin and significantly reduce fitness in media without colistin. PET-B and PET-C were phenotypically distinct from bonafide PETs; neither impacted colistin susceptibility nor caused considerable fitness cost. Strikingly, we found for the first time that different PETs selectively modify different phosphates of lipid A; MCR-1, MCR-3, and PET-C selectively modify the 4'-phosphate, whereas MCR-9 and EptA modify the 1-phosphate. However, 4'-phosphate modifications facilitated by MCR-1 and -3 are associated with lowered colistin susceptibility and low toxicity. Our results suggest that PETs have a wide phenotypic diversity and that increased colistin resistance is associated with specific lipid A modification patterns that have been largely unexplored thus far. IMPORTANCE: Rising levels of resistance to increasing numbers of antimicrobials have led to the revival of last resort antibiotic colistin. Unfortunately, resistance to colistin is also spreading in the form of mcr genes, making it essential to (i) improve the identification of resistant bacteria to allow clinicians to prescribe effective drug regimens and (ii) develop new combination therapies effective at targeting resistant bacteria. Our results demonstrate that PETs, including MCR variants, are site-selective in Escherichia coli and that site-selectivity correlates with the level of susceptibility and fitness costs conferred by certain PETs. Site selectivity associated with a given PET may not only help predict colistin resistance phenotypes but may also provide an avenue to (i) improve drug regimens and (ii) develop new combination therapies to better combat colistin-resistant bacteria. | 2024 | 39611852 |
| 4836 | 18 | 0.9997 | Genes and spectrum: the theoretical limits. Antibiotic resistance can result either from mutations within a chromosomal gene or from mobile genes imported from outside. In the last 15 years, some of these mobile genes have shown a propensity to adapt to successive antibiotic challenges, the most versatile being the class A beta-lactamases. The TEM and SHV beta-lactamase nuclei, usually after one initial critical mutation, allow a series of successive mutations that increase the spectrum to hydrolyze most cephalosporins. The class C beta-lactamases also show some versatility; while it migrates from the chromosome, subtle changes can occur in the gene to broaden the spectrum. Trimethoprim resistance has shown less adaptability in gram-negative bacteria, but in gram-positive organisms the plasmid has captured the chromosomal dihydrofolate reductase of Staphylococcus epidermidis, and a minimal number of changes have occurred that decrease the binding of trimethroprim. Other resistance mechanisms appear less adaptable, relying rather on the importation of new genes to cope with new challenges. | 1998 | 9710668 |
| 4314 | 19 | 0.9997 | Cephalosporin resistance among animal-associated Enterobacteria: a current perspective. Beta-lactam antimicrobials are an important class of drugs used for the treatment of infection. Resistance can arise by several mechanisms, including the acquisition of genes encoding beta-lactamases from other bacteria, alterations in cell membrane permeability and over expression of endogenous beta-lactamases. The acquisition of beta-lactamase resistance genes by both Salmonella and Escherichia coli appears to be on the rise, which may pose potential problems for the treatment of infections in both human and animal medicine. The prudent use of clinically important antimicrobials is therefore critical to maintain their effectiveness. Where possible, the use of newer generation cephalosporins should be limited in veterinary medicine. | 2005 | 15954857 |