# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 501 | 0 | 1.0000 | Centromere anatomy in the multidrug-resistant pathogen Enterococcus faecium. Multidrug-resistant variants of the opportunistic human pathogen Enterococcus have recently emerged as leading agents of nosocomial infection. The acquisition of plasmid-borne resistance genes is a driving force in antibiotic-resistance evolution in enterococci. The segregation locus of a high-level gentamicin-resistance plasmid, pGENT, in Enterococcus faecium was identified and dissected. This locus includes overlapping genes encoding PrgP, a member of the ParA superfamily of segregation proteins, and PrgO, a site-specific DNA binding homodimer that recognizes the cenE centromere upstream of prgPO. The centromere has a distinctive organization comprising three subsites, CESII separates CESI and CESIII, each of which harbors seven TATA boxes spaced by half-helical turns. PrgO independently binds both CESI and CESIII, but with different affinities. The topography of the complex was probed by atomic force microscopy, revealing discrete PrgO foci positioned asymmetrically at the CESI and CESIII subsites. Bending analysis demonstrated that cenE is intrinsically curved. The organization of the cenE site and of certain other plasmid centromeres mirrors that of yeast centromeres, which may reflect a common architectural requirement during assembly of the mitotic apparatus in yeast and bacteria. Moreover, segregation modules homologous to that of pGENT are widely disseminated on vancomycin and other resistance plasmids in enterococci. An improved understanding of segrosome assembly may highlight new interventions geared toward combating antibiotic resistance in these insidious pathogens. | 2008 | 18245388 |
| 9230 | 1 | 0.9959 | Phage defence loci of Streptococcus thermophilus-tip of the anti-phage iceberg? Bacteria possess (bacterio)phage defence systems to ensure their survival. The thermophilic lactic acid bacterium, Streptococcus thermophilus, which is used in dairy fermentations, harbours multiple CRISPR-Cas and restriction and modification (R/M) systems to protect itself against phage attack, with limited reports on other types of phage-resistance. Here, we describe the systematic identification and functional analysis of the phage resistome of S. thermophilus using a collection of 27 strains as representatives of the species. In addition to CRISPR-Cas and R/M systems, we uncover nine distinct phage-resistance systems including homologues of Kiwa, Gabija, Dodola, defence-associated sirtuins and classical lactococcal/streptococcal abortive infection systems. The genes encoding several of these newly identified S. thermophilus antiphage systems are located in proximity to the genetic determinants of CRISPR-Cas systems thus constituting apparent Phage Defence Islands. Other phage-resistance systems whose encoding genes are not co-located with genes specifying CRISPR-Cas systems may represent anchors to identify additional Defence Islands harbouring, as yet, uncharacterised phage defence systems. We estimate that up to 2.5% of the genetic material of the analysed strains is dedicated to phage defence, highlighting that phage-host antagonism plays an important role in driving the evolution and shaping the composition of dairy streptococcal genomes. | 2024 | 39315705 |
| 8359 | 2 | 0.9959 | Comparative Genomic Analysis of Acanthamoeba Endosymbionts Highlights the Role of Amoebae as a "Melting Pot" Shaping the Rickettsiales Evolution. Amoebae have been considered as a genetic "melting pot" for its symbionts, facilitating genetic exchanges of the bacteria that co-inhabit the same host. To test the "melting pot" hypothesis, we analyzed six genomes of amoeba endosymbionts within Rickettsiales, four of which belong to Holosporaceae family and two to Candidatus Midichloriaceae. For the first time, we identified plasmids in obligate amoeba endosymbionts, which suggests conjugation as a potential mechanism for lateral gene transfers (LGTs) that underpin the "melting pot" hypothesis. We found strong evidence of recent LGTs between the Rickettsiales amoeba endosymbionts, suggesting that the LGTs are continuous and ongoing. In addition, comparative genomic and phylogenomic analyses revealed pervasive and recurrent LGTs between Rickettsiales and distantly related amoeba-associated bacteria throughout the Rickettsiales evolution. Many of these exchanged genes are important for amoeba-symbiont interactions, including genes in transport system, antibiotic resistance, stress response, and bacterial virulence, suggesting that LGTs have played important roles in the adaptation of endosymbionts to their intracellular habitats. Surprisingly, we found little evidence of LGTs between amoebae and their bacterial endosymbionts. Our study strongly supports the "melting pot" hypothesis and highlights the role of amoebae in shaping the Rickettsiales evolution. | 2017 | 29177480 |
| 9726 | 3 | 0.9959 | The complex resistomes of Paenibacillaceae reflect diverse antibiotic chemical ecologies. The ecology of antibiotic resistance involves the interplay of a long natural history of antibiotic production in the environment, and the modern selection of resistance in pathogens through human use of these drugs. Important components of the resistome are intrinsic resistance genes of environmental bacteria, evolved and acquired over millennia, and their mobilization, which drives dissemination in pathogens. Understanding the dynamics and evolution of resistance across bacterial taxa is essential to address the current crisis in drug-resistant infections. Here we report the exploration of antibiotic resistance in the Paenibacillaceae prompted by our discovery of an ancient intrinsic resistome in Paenibacillus sp. LC231, recovered from the isolated Lechuguilla cave environment. Using biochemical and gene expression analysis, we have mined the resistome of the second member of the Paenibacillaceae family, Brevibacillus brevis VM4, which produces several antimicrobial secondary metabolites. Using phylogenomics, we show that Paenibacillaceae resistomes are in flux, evolve mostly independent of secondary metabolite biosynthetic diversity, and are characterized by cryptic, redundant, pseudoparalogous, and orthologous genes. We find that in contrast to pathogens, mobile genetic elements are not significantly responsible for resistome remodeling. This offers divergent modes of resistome development in pathogens and environmental bacteria. | 2018 | 29259290 |
| 8274 | 4 | 0.9958 | Exposure and resistance to lantibiotics impact microbiota composition and function. The intestinal microbiota is composed of hundreds of distinct microbial species that interact with each other and their mammalian host. Antibiotic exposure dramatically impacts microbiota compositions and leads to acquisition of antibiotic-resistance genes. Lantibiotics are ribosomally synthesized and post-translationally modified peptides produced by some bacterial strains to inhibit the growth of competing bacteria. Nisin A is a lantibiotic produced by Lactococcus lactis that is commonly added to food products to reduce contamination with Gram-positive pathogens. Little is known, however, about lantibiotic-resistance of commensal bacteria inhabiting the human intestine. Herein, we demonstrate that Nisin A administration to mice alters fecal microbiome compositions and the concentration of taurine-conjugated primary bile acids. Lantibiotic Resistance System genes (LRS) are encoded by lantibiotic-producing bacterial strains but, we show, are also prevalent in microbiomes across human cohorts spanning vastly different lifestyles and 5 continents. Bacterial strains encoding LRS have enhanced in vivo fitness upon dietary exposure to Nisin A but reduced fitness in the absence of lantibiotic pressure. Differential binding of host derived, secreted IgA contributes to fitness discordance between bacterial strains encoding or lacking LRS. Although LRS are associated with mobile genetic elements, sequence comparisons of LRS encoded by distinct bacterial species suggest they have been long-term components of their respective genomes. Our study reveals the prevalence, abundance and physiologic significance of an underappreciated subset of antimicrobial resistance genes encoded by commensal bacterial species constituting the human gut microbiome, and provides insights that will guide development of microbiome augmenting strategies. | 2023 | 38234830 |
| 228 | 5 | 0.9958 | Resistance to nonribosomal peptide antibiotics mediated by D-stereospecific peptidases. Nonribosomal peptide antibiotics, including polymyxin, vancomycin, and teixobactin, most of which contain D-amino acids, are highly effective against multidrug-resistant bacteria. However, overusing antibiotics while ignoring the risk of resistance arising has inexorably led to widespread emergence of resistant bacteria. Therefore, elucidation of the emerging mechanisms of resistance to nonribosomal peptide antibiotics is critical to their implementation. Here we describe a networking-associated genome-mining platform for linking biosynthetic building blocks to resistance components associated with biosynthetic gene clusters. By applying this approach to 5,585 complete bacterial genomes spanning the entire domain of bacteria, with subsequent chemical and enzymatic analyses, we demonstrate a mechanism of resistance toward nonribosomal peptide antibiotics that is based on hydrolytic cleavage by D-stereospecific peptidases. Our finding reveals both the widespread distribution and broad-spectrum resistance potential of D-stereospecific peptidases, providing a potential early indicator of antibiotic resistance to nonribosomal peptide antibiotics. | 2018 | 29483640 |
| 9213 | 6 | 0.9958 | Emergence of antibiotic-resistant extremophiles (AREs). Excessive use of antibiotics in recent years has produced bacteria that are resistant to a wide array of antibiotics. Several genetic and non-genetic elements allow microorganisms to adapt and thrive under harsh environmental conditions such as lethal doses of antibiotics. We attempt to classify these microorganisms as antibiotic-resistant extremophiles (AREs). AREs develop strategies to gain greater resistance to antibiotics via accumulation of multiple genes or plasmids that harbor genes for multiple drug resistance (MDR). In addition to their altered expression of multiple genes, AREs also survive by producing enzymes such as penicillinase that inactivate antibiotics. It is of interest to identify the underlying molecular mechanisms by which the AREs are able to survive in the presence of wide arrays of high-dosage antibiotics. Technologically, "omics"-based approaches such as genomics have revealed a wide array of genes differentially expressed in AREs. Proteomics studies with 2DE, MALDI-TOF, and MS/MS have identified specific proteins, enzymes, and pumps that function in the adaptation mechanisms of AREs. This article discusses the molecular mechanisms by which microorganisms develop into AREs and how "omics" approaches can identify the genetic elements of these adaptation mechanisms. These objectives will assist the development of strategies and potential therapeutics to treat outbreaks of pathogenic microorganisms in the future. | 2012 | 22907125 |
| 9849 | 7 | 0.9957 | Analysis of antibiotic resistance regions in Gram-negative bacteria. Antibiotic resistance in Gram-negative bacteria is often due to the acquisition of resistance genes from a shared pool. In multiresistant isolates these genes, together with associated mobile elements, may be found in complex conglomerations on plasmids or on the chromosome. Analysis of available sequences reveals that these multiresistance regions (MRR) are modular, mosaic structures composed of different combinations of components from a limited set arranged in a limited number of ways. Components common to different MRR provide targets for homologous recombination, allowing these regions to evolve by combinatorial evolution, but our understanding of this process is far from complete. Advances in technology are leading to increasing amounts of sequence data, but currently available automated annotation methods usually focus on identifying ORFs and predicting protein function by homology. In MRR, where the genes are often well characterized, the challenge is to identify precisely which genes are present and to define the boundaries of complete and fragmented mobile elements. This review aims to summarize the types of mobile elements involved in multiresistance in Gram-negative bacteria and their associations with particular resistance genes, to describe common components of MRR and to illustrate methods for detailed analysis of these regions. | 2011 | 21564142 |
| 9234 | 8 | 0.9957 | CRISPR provides acquired resistance against viruses in prokaryotes. Clustered regularly interspaced short palindromic repeats (CRISPR) are a distinctive feature of the genomes of most Bacteria and Archaea and are thought to be involved in resistance to bacteriophages. We found that, after viral challenge, bacteria integrated new spacers derived from phage genomic sequences. Removal or addition of particular spacers modified the phage-resistance phenotype of the cell. Thus, CRISPR, together with associated cas genes, provided resistance against phages, and resistance specificity is determined by spacer-phage sequence similarity. | 2007 | 17379808 |
| 9235 | 9 | 0.9957 | Investigating the Genomic Background of CRISPR-Cas Genomes for CRISPR-Based Antimicrobials. CRISPR-Cas systems are an adaptive immunity that protects prokaryotes against foreign genetic elements. Genetic templates acquired during past infection events enable DNA-interacting enzymes to recognize foreign DNA for destruction. Due to the programmability and specificity of these genetic templates, CRISPR-Cas systems are potential alternative antibiotics that can be engineered to self-target antimicrobial resistance genes on the chromosome or plasmid. However, several fundamental questions remain to repurpose these tools against drug-resistant bacteria. For endogenous CRISPR-Cas self-targeting, antimicrobial resistance genes and functional CRISPR-Cas systems have to co-occur in the target cell. Furthermore, these tools have to outplay DNA repair pathways that respond to the nuclease activities of Cas proteins, even for exogenous CRISPR-Cas delivery. Here, we conduct a comprehensive survey of CRISPR-Cas genomes. First, we address the co-occurrence of CRISPR-Cas systems and antimicrobial resistance genes in the CRISPR-Cas genomes. We show that the average number of these genes varies greatly by the CRISPR-Cas type, and some CRISPR-Cas types (IE and IIIA) have over 20 genes per genome. Next, we investigate the DNA repair pathways of these CRISPR-Cas genomes, revealing that the diversity and frequency of these pathways differ by the CRISPR-Cas type. The interplay between CRISPR-Cas systems and DNA repair pathways is essential for the acquisition of new spacers in CRISPR arrays. We conduct simulation studies to demonstrate that the efficiency of these DNA repair pathways may be inferred from the time-series patterns in the RNA structure of CRISPR repeats. This bioinformatic survey of CRISPR-Cas genomes elucidates the necessity to consider multifaceted interactions between different genes and systems, to design effective CRISPR-based antimicrobials that can specifically target drug-resistant bacteria in natural microbial communities. | 2022 | 35692726 |
| 9342 | 10 | 0.9957 | Natural transformation in Gram-negative bacteria thriving in extreme environments: from genes and genomes to proteins, structures and regulation. Extremophilic prokaryotes live under harsh environmental conditions which require far-reaching cellular adaptations. The acquisition of novel genetic information via natural transformation plays an important role in bacterial adaptation. This mode of DNA transfer permits the transfer of genetic information between microorganisms of distant evolutionary lineages and even between members of different domains. This phenomenon, known as horizontal gene transfer (HGT), significantly contributes to genome plasticity over evolutionary history and is a driving force for the spread of fitness-enhancing functions including virulence genes and antibiotic resistances. In particular, HGT has played an important role for adaptation of bacteria to extreme environments. Here, we present a survey of the natural transformation systems in bacteria that live under extreme conditions: the thermophile Thermus thermophilus and two desiccation-resistant members of the genus Acinetobacter such as Acinetobacter baylyi and Acinetobacter baumannii. The latter is an opportunistic pathogen and has become a world-wide threat in health-care institutions. We highlight conserved and unique features of the DNA transporter in Thermus and Acinetobacter and present tentative models of both systems. The structure and function of both DNA transporter are described and the mechanism of DNA uptake is discussed. | 2021 | 34542714 |
| 9693 | 11 | 0.9957 | Antibody-mediated crosslinking of gut bacteria hinders the spread of antibiotic resistance. The body is home to a diverse microbiota, mainly in the gut. Resistant bacteria are selected by antibiotic treatments, and once resistance becomes widespread in a population of hosts, antibiotics become useless. Here, we develop a multiscale model of the interaction between antibiotic use and resistance spread in a host population, focusing on an important aspect of within-host immunity. Antibodies secreted in the gut enchain bacteria upon division, yielding clonal clusters of bacteria. We demonstrate that immunity-driven bacteria clustering can hinder the spread of a novel resistant bacterial strain in a host population. We quantify this effect both in the case where resistance preexists and in the case where acquiring a new resistance mutation is necessary for the bacteria to spread. We further show that the reduction of spread by clustering can be countered when immune hosts are silent carriers, and are less likely to get treated, and/or have more contacts. We demonstrate the robustness of our findings to including stochastic within-host bacterial growth, a fitness cost of resistance, and its compensation. Our results highlight the importance of interactions between immunity and the spread of antibiotic resistance, and argue in the favor of vaccine-based strategies to combat antibiotic resistance. | 2019 | 30957218 |
| 9401 | 12 | 0.9957 | Enterococcus faecalis CRISPR-Cas Is a Robust Barrier to Conjugative Antibiotic Resistance Dissemination in the Murine Intestine. CRISPR-Cas systems are barriers to horizontal gene transfer (HGT) in bacteria. Little is known about CRISPR-Cas interactions with conjugative plasmids, and studies investigating CRISPR-Cas/plasmid interactions in in vivo models relevant to infectious disease are lacking. These are significant gaps in knowledge because conjugative plasmids disseminate antibiotic resistance genes among pathogens in vivo, and it is essential to identify strategies to reduce the spread of these elements. We use enterococci as models to understand the interactions of CRISPR-Cas with conjugative plasmids. Enterococcus faecalis is a native colonizer of the mammalian intestine and harbors pheromone-responsive plasmids (PRPs). PRPs mediate inter- and intraspecies transfer of antibiotic resistance genes. We assessed E. faecalis CRISPR-Cas anti-PRP activity in the mouse intestine and under different in vitro conditions. We observed striking differences in CRISPR-Cas efficiency in vitro versus in vivo With few exceptions, CRISPR-Cas blocked intestinal PRP dissemination, while in vitro, the PRP frequently escaped CRISPR-Cas defense. Our results further the understanding of CRISPR-Cas biology by demonstrating that standard in vitro experiments do not adequately model the in vivo antiplasmid activity of CRISPR-Cas. Additionally, our work identifies several variables that impact the apparent in vitro antiplasmid activity of CRISPR-Cas, including planktonic versus biofilm settings, different donor-to-recipient ratios, production of a plasmid-encoded bacteriocin, and the time point at which matings are sampled. Our results are clinically significant because they demonstrate that barriers to HGT encoded by normal (healthy) human microbiota can have significant impacts on in vivo antibiotic resistance dissemination.IMPORTANCE CRISPR-Cas is a type of immune system in bacteria that is hypothesized to be a natural impediment to the spread of antibiotic resistance genes. In this study, we directly assessed the impact of CRISPR-Cas on antibiotic resistance dissemination in the mammalian intestine and under different in vitro conditions. We observed a robust effect of CRISPR-Cas on in vivo but not in vitro dissemination of antibiotic resistance plasmids in the native mammalian intestinal colonizer Enterococcus faecalis We conclude that standard in vitro experiments currently do not appropriately model the in vivo conditions where antibiotic resistance dissemination occurs between E. faecalis strains in the intestine. Moreover, our results demonstrate that CRISPR-Cas present in native members of the mammalian intestinal microbiota can block the spread of antibiotic resistance plasmids. | 2019 | 31341074 |
| 9362 | 13 | 0.9957 | Rapid diversification of coevolving marine Synechococcus and a virus. Marine viruses impose a heavy mortality on their host bacteria, whereas at the same time the degree of viral resistance in marine bacteria appears to be high. Antagonistic coevolution--the reciprocal evolutionary change of interacting species--might reconcile these observations, if it leads to rapid and dynamic levels of viral resistance. Here we demonstrate the potential for extensive antagonistic coevolution between the ecologically important marine cyanobacterium Synechococcus and a lytic virus. In a 6-mo-long replicated chemostat experiment, Synechococcus sp. WH7803 and the virus (RIM8) underwent multiple coevolutionary cycles, leading to the rapid diversification of both host and virus. Over the course of the experiment, we detected between 4 and 13 newly evolved viral phenotypes (differing in host range) and between 4 and 11 newly evolved Synechococcus phenotypes (differing in viral resistance) in each chemostat. Genomic analysis of isolates identified several candidate genes in both the host and virus that might influence their interactions. Notably, none of the viral candidates were tail fiber genes, thought to be the primary determinants of host range in tailed bacteriophages, highlighting the difficulty in generalizing results from bacteriophage infecting γ-Proteobacteria. Finally, we show that pairwise virus-host coevolution may have broader community consequences; coevolution in the chemostat altered the sensitivity of Synechoccocus to a diverse suite of viruses, as well as the virus' ability to infect additional Synechococcus strains. Our results indicate that rapid coevolution may contribute to the generation and maintenance of Synechococcus and virus diversity and thereby influence viral-mediated mortality of these key marine bacteria. | 2012 | 22388749 |
| 4436 | 14 | 0.9957 | Bacterial resistance to vancomycin: five genes and one missing hydrogen bond tell the story. A plasmid-borne transposon encodes enzymes and regulator proteins that confer resistance of enterococcal bacteria to the antibiotic vancomycin. Purification and characterization of individual proteins encoded by this operon has helped to elucidate the molecular basis of vancomycin resistance. This new understanding provides opportunities for intervention to reverse resistance. | 1996 | 8807824 |
| 9826 | 15 | 0.9957 | Horizontal genetic exchange, evolution, and spread of antibiotic resistance in bacteria. Some transformable bacteria have acquired target-mediated antibiotic resistance by horizontal genetic exchange of fragments of chromosomal genes. The resistant strains express variants of the antibiotic target that are metabolically active but exhibit a lowered affinity for the antibiotic. The alleles encoding these resistant proteins are mosaics comprising DNA derived from the host and other bacteria, often members of a different species. Examples include penicillin-resistant penicillin-binding proteins (PBPs) in Streptococcus pneumoniae and the pathogenic Neisseria species and sulfonamide-resistant dihydropterate synthase in Neisseria meningitidis. Distinct mosaic alleles encoding antibiotic resistance have arisen on multiple occasions, indicating the mobility of chromosomal genes in these species. Mosaic genes can arise at any chromosomal locus, and S. pneumoniae organisms with high-level penicillin resistance have acquired mosaic PBP genes at three bacterial bpb loci. Furthermore, horizontal genetic exchange permits movement of alleles among bacterial lineages, increasing the opportunities for the spread of antibiotic resistance. | 1998 | 9710667 |
| 9233 | 16 | 0.9957 | The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. Bacteria and Archaea have developed several defence strategies against foreign nucleic acids such as viral genomes and plasmids. Among them, clustered regularly interspaced short palindromic repeats (CRISPR) loci together with cas (CRISPR-associated) genes form the CRISPR/Cas immune system, which involves partially palindromic repeats separated by short stretches of DNA called spacers, acquired from extrachromosomal elements. It was recently demonstrated that these variable loci can incorporate spacers from infecting bacteriophages and then provide immunity against subsequent bacteriophage infections in a sequence-specific manner. Here we show that the Streptococcus thermophilus CRISPR1/Cas system can also naturally acquire spacers from a self-replicating plasmid containing an antibiotic-resistance gene, leading to plasmid loss. Acquired spacers that match antibiotic-resistance genes provide a novel means to naturally select bacteria that cannot uptake and disseminate such genes. We also provide in vivo evidence that the CRISPR1/Cas system specifically cleaves plasmid and bacteriophage double-stranded DNA within the proto-spacer, at specific sites. Our data show that the CRISPR/Cas immune system is remarkably adapted to cleave invading DNA rapidly and has the potential for exploitation to generate safer microbial strains. | 2010 | 21048762 |
| 4371 | 17 | 0.9956 | Independent origins and evolution of the secondary replicons of the class Gammaproteobacteria. Multipartite genomes, consisting of more than one replicon, have been found in approximately 10 % of bacteria, many of which belong to the phylum Proteobacteria. Many aspects of their origin and evolution, and the possible advantages related to this type of genome structure, remain to be elucidated. Here, we performed a systematic analysis of the presence and distribution of multipartite genomes in the class Gammaproteobacteria, which includes several genera with diverse lifestyles. Within this class, multipartite genomes are mainly found in the order Alteromonadales (mostly in the genus Pseudoalteromonas) and in the family Vibrionaceae. Our data suggest that the emergence of secondary replicons in Gammaproteobacteria is rare and that they derive from plasmids. Despite their multiple origins, we highlighted the presence of evolutionary trends such as the inverse proportionality of the genome to chromosome size ratio, which appears to be a general feature of bacteria with multipartite genomes irrespective of taxonomic group. We also highlighted some functional trends. The core gene set of the secondary replicons is extremely small, probably limited to essential genes or genes that favour their maintenance in the genome, while the other genes are less conserved. This hypothesis agrees with the idea that the primary advantage of secondary replicons could be to facilitate gene acquisition through horizontal gene transfer, resulting in replicons enriched in genes associated with adaptation to different ecological niches. Indeed, secondary replicons are enriched both in genes that could promote adaptation to harsh environments, such as those involved in antibiotic, biocide and metal resistance, and in functional categories related to the exploitation of environmental resources (e.g. carbohydrates), which can complement chromosomal functions. | 2023 | 37185344 |
| 4246 | 18 | 0.9956 | Bacteriocins to Thwart Bacterial Resistance in Gram Negative Bacteria. An overuse of antibiotics both in human and animal health and as growth promoters in farming practices has increased the prevalence of antibiotic resistance in bacteria. Antibiotic resistant and multi-resistant bacteria are now considered a major and increasing threat by national health agencies, making the need for novel strategies to fight bugs and super bugs a first priority. In particular, Gram-negative bacteria are responsible for a high proportion of nosocomial infections attributable for a large part to Enterobacteriaceae, such as pathogenic Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. To cope with their highly competitive environments, bacteria have evolved various adaptive strategies, among which the production of narrow spectrum antimicrobial peptides called bacteriocins and specifically microcins in Gram-negative bacteria. They are produced as precursor peptides that further undergo proteolytic cleavage and in many cases more or less complex posttranslational modifications, which contribute to improve their stability and efficiency. Many have a high stability in the gastrointestinal tract where they can target a single pathogen whilst only slightly perturbing the gut microbiota. Several microcins and antibiotics can bind to similar bacterial receptors and use similar pathways to cross the double-membrane of Gram-negative bacteria and reach their intracellular targets, which they also can share. Consequently, bacteria may use common mechanisms of resistance against microcins and antibiotics. This review describes both unmodified and modified microcins [lasso peptides, siderophore peptides, nucleotide peptides, linear azole(in)e-containing peptides], highlighting their potential as weapons to thwart bacterial resistance in Gram-negative pathogens and discusses the possibility of cross-resistance and co-resistance occurrence between antibiotics and microcins in Gram-negative bacteria. | 2020 | 33240239 |
| 303 | 19 | 0.9956 | Substrate Recognition by a Colistin Resistance Enzyme from Moraxella catarrhalis. Lipid A phosphoethanolamine (PEtN) transferases render bacteria resistant to the last resort antibiotic colistin. The recent discoveries of pathogenic bacteria harboring plasmid-borne PEtN transferase ( mcr) genes have illustrated the serious potential for wide dissemination of these resistance elements. The origin of mcr-1 is traced to Moraxella species co-occupying environmental niches with Enterobacteriaceae. Here, we describe the crystal structure of the catalytic domain of the chromosomally encoded colistin resistance PEtN transferase, ICR (Mc) (for intrinsic colistin resistance) of Moraxella catarrhalis. The ICR (Mc) structure in complex with PEtN reveals key molecular details including specific residues involved in catalysis and PEtN binding. It also demonstrates that ICR (Mc) catalytic domain dimerization is required for substrate binding. Our structure-guided phylogenetic analysis provides sequence signatures defining potentially colistin-active representatives in this enzyme family. Combined, these results advance the molecular and mechanistic understanding of PEtN transferases and illuminate their origins. | 2018 | 29631403 |