# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 8362 | 0 | 0.9963 | Lifestyle evolution in symbiotic bacteria: insights from genomics. Bacteria that live only in eukaryotic cells and tissues, including chronic pathogens and mutualistic bacteriocyte associates, often possess a distinctive set of genomic traits, including reduced genome size, biased nucleotide base composition and fast polypeptide evolution. These phylogenetically diverse bacteria have lost certain functional categories of genes, including DNA repair genes, which affect mutational patterns. However, pathogens and mutualistic symbionts retain loci that underlie their unique interaction types, such as genes enabling nutrient provisioning by mutualistic bacteria-inhabiting animals. Recent genomic studies suggest that many of these bacteria are irreversibly specialized, precluding shifts between pathogenesis and mutualism. | 2000 | 10884696 |
| 8267 | 1 | 0.9963 | Why put up with immunity when there is resistance: an excursion into the population and evolutionary dynamics of restriction-modification and CRISPR-Cas. Bacteria can readily generate mutations that prevent bacteriophage (phage) adsorption and thus make bacteria resistant to infections with these viruses. Nevertheless, the majority of bacteria carry complex innate and/or adaptive immune systems: restriction-modification (RM) and CRISPR-Cas, respectively. Both RM and CRISPR-Cas are commonly assumed to have evolved and be maintained to protect bacteria from succumbing to infections with lytic phage. Using mathematical models and computer simulations, we explore the conditions under which selection mediated by lytic phage will favour such complex innate and adaptive immune systems, as opposed to simple envelope resistance. The results of our analysis suggest that when populations of bacteria are confronted with lytic phage: (i) In the absence of immunity, resistance to even multiple bacteriophage species with independent receptors can evolve readily. (ii) RM immunity can benefit bacteria by preventing phage from invading established bacterial populations and particularly so when there are multiple bacteriophage species adsorbing to different receptors. (iii) Whether CRISPR-Cas immunity will prevail over envelope resistance depends critically on the number of steps in the coevolutionary arms race between the bacteria-acquiring spacers and the phage-generating CRISPR-escape mutants. We discuss the implications of these results in the context of the evolution and maintenance of RM and CRISPR-Cas and highlight fundamental questions that remain unanswered. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'. | 2019 | 30905282 |
| 8268 | 2 | 0.9961 | Sustained coevolution of phage Lambda and Escherichia coli involves inner- as well as outer-membrane defences and counter-defences. Bacteria often evolve resistance to phage through the loss or modification of cell surface receptors. In Escherichia coli and phage λ, such resistance can catalyze a coevolutionary arms race focused on host and phage structures that interact at the outer membrane. Here, we analyse another facet of this arms race involving interactions at the inner membrane, whereby E. coli evolves mutations in mannose permease-encoding genes manY and manZ that impair λ's ability to eject its DNA into the cytoplasm. We show that these man mutants arose concurrently with the arms race at the outer membrane. We tested the hypothesis that λ evolved an additional counter-defence that allowed them to infect bacteria with deleted man genes. The deletions severely impaired the ancestral λ, but some evolved phage grew well on the deletion mutants, indicating that they regained infectivity by evolving the ability to infect hosts independently of the mannose permease. This coevolutionary arms race fulfils the model of an inverse gene-for-gene infection network. Taken together, the interactions at both the outer and inner membranes reveal that coevolutionary arms races can be richer and more complex than is often appreciated. | 2021 | 34032565 |
| 8358 | 3 | 0.9961 | Genomic features underlying the evolutionary transitions of Apibacter to honey bee gut symbionts. The gut bacteria of honey bee recognized as a mutualistic partner with the insect host might have originated from a free-living or parasitic lifestyle. However, little is known about the genomic features underlying this lifestyle transition. Here we compared the genomes of bee gut bacteria Apibacter with their close relatives living in different lifestyles. We found that despite general reduction in the Apibacter genome, genes involved in amino acid synthesis and monosaccharide detoxification were retained, which is putatively beneficial to the host. Interestingly, the microaerobic Apibacter species specifically acquired genes encoding for the nitrate respiration (NAR). These together with nitrate transporter and enzymatic cofactor synthesis genes were found clustered in the genomes. The NAR system is also conserved in the cohabitating bee gut microbe Snodgrassella, although with a different structure. This convergence suggests a key role of respiratory nitrate reduction for microaerophilic microbiomes to colonize bee gut epithelium. Genes involved in lipid, histidine degradation were found partially or completely lost in Apibacter. Particularly, genes encoding for the conversion to the toxic intermediates in phenylacetate degradation, as well as other potential virulence factors, are specifically lost in Apibacter group. Antibiotic resistance genes are only sporadically distributed among Apibacter species, but are prevalent in their relatives, which may be related to the remotely living feature and less exposure to antibiotics of their bee hosts. Collectively, this study advanced our knowledge of genomic features specialized to bee gut symbionts. | 2022 | 33811731 |
| 9600 | 4 | 0.9961 | Novel "Superspreader" Bacteriophages Promote Horizontal Gene Transfer by Transformation. Bacteriophages infect an estimated 10(23) to 10(25) bacterial cells each second, many of which carry physiologically relevant plasmids (e.g., those encoding antibiotic resistance). However, even though phage-plasmid interactions occur on a massive scale and have potentially significant evolutionary, ecological, and biomedical implications, plasmid fate upon phage infection and lysis has not been investigated to date. Here we show that a subset of the natural lytic phage population, which we dub "superspreaders," releases substantial amounts of intact, transformable plasmid DNA upon lysis, thereby promoting horizontal gene transfer by transformation. Two novel Escherichia coli phage superspreaders, SUSP1 and SUSP2, liberated four evolutionarily distinct plasmids with equal efficiency, including two close relatives of prominent antibiotic resistance vectors in natural environments. SUSP2 also mediated the extensive lateral transfer of antibiotic resistance in unbiased communities of soil bacteria from Maryland and Wyoming. Furthermore, the addition of SUSP2 to cocultures of kanamycin-resistant E. coli and kanamycin-sensitive Bacillus sp. bacteria resulted in roughly 1,000-fold more kanamycin-resistant Bacillus sp. bacteria than arose in phage-free controls. Unlike many other lytic phages, neither SUSP1 nor SUSP2 encodes homologs to known hydrolytic endonucleases, suggesting a simple potential mechanism underlying the superspreading phenotype. Consistent with this model, the deletion of endonuclease IV and the nucleoid-disrupting protein ndd from coliphage T4, a phage known to extensively degrade chromosomal DNA, significantly increased its ability to promote plasmid transformation. Taken together, our results suggest that phage superspreaders may play key roles in microbial evolution and ecology but should be avoided in phage therapy and other medical applications. IMPORTANCE: Bacteriophages (phages), viruses that infect bacteria, are the planet's most numerous biological entities and kill vast numbers of bacteria in natural environments. Many of these bacteria carry plasmids, extrachromosomal DNA elements that frequently encode antibiotic resistance. However, it is largely unknown whether plasmids are destroyed during phage infection or released intact upon phage lysis, whereupon their encoded resistance could be acquired and manifested by other bacteria (transformation). Because phages are being developed to combat antibiotic-resistant bacteria and because transformation is a principal form of horizontal gene transfer, this question has important implications for biomedicine and microbial evolution alike. Here we report the isolation and characterization of two novel Escherichia coli phages, dubbed "superspreaders," that promote extensive plasmid transformation and efficiently disperse antibiotic resistance genes. Our work suggests that phage superspreaders are not suitable for use in medicine but may help drive bacterial evolution in natural environments. | 2017 | 28096488 |
| 8264 | 5 | 0.9961 | Anti-CRISPR Phages Cooperate to Overcome CRISPR-Cas Immunity. Some phages encode anti-CRISPR (acr) genes, which antagonize bacterial CRISPR-Cas immune systems by binding components of its machinery, but it is less clear how deployment of these acr genes impacts phage replication and epidemiology. Here, we demonstrate that bacteria with CRISPR-Cas resistance are still partially immune to Acr-encoding phage. As a consequence, Acr-phages often need to cooperate in order to overcome CRISPR resistance, with a first phage blocking the host CRISPR-Cas immune system to allow a second Acr-phage to successfully replicate. This cooperation leads to epidemiological tipping points in which the initial density of Acr-phage tips the balance from phage extinction to a phage epidemic. Furthermore, both higher levels of CRISPR-Cas immunity and weaker Acr activities shift the tipping points toward higher initial phage densities. Collectively, these data help elucidate how interactions between phage-encoded immune suppressors and the CRISPR systems they target shape bacteria-phage population dynamics. | 2018 | 30033365 |
| 9233 | 6 | 0.9961 | 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 |
| 9202 | 7 | 0.9960 | Microbial avirulence determinants: guided missiles or antigenic flak? SUMMARY Avirulence (avr) determinants are incompatibility factors which elicit host plant defence responses in a gene-for-gene manner. They are produced by fungi, bacteria and viruses, and their recognition by resistance genes has been extensively studied for decades. But why should a microbe keep a molecule that allows it to be recognized? One argument is that avr genes perform some essential function and must be kept despite giving the pathogen away. Many bacterial avr determinants have been shown to be effectors, which contribute to virulence and aggressiveness. If this were always the case, mutants lacking these essential molecules would be at a serious disadvantage. Some disadvantage has been shown for a small number, but for the majority there is no effect on virulence. This has been explained by functional redundancy for bacterial and fungal avr determinants, with other molecules compensating for the deletion of these essential genes. However, this argument is counter-intuitive because by definition these individual genes are no longer essential; so why keep them? With increasing numbers of avr genes being identified, efforts to elucidate their function are increasing. In this review, we take stock of the accumulating literature, and consider what the real function of avr determinants might be. | 2005 | 20565679 |
| 8363 | 8 | 0.9960 | Hundreds of antimicrobial peptides create a selective barrier for insect gut symbionts. The spatial organization of gut microbiota is crucial for the functioning of the gut ecosystem, although the mechanisms that organize gut bacterial communities in microhabitats are only partially understood. The gut of the insect Riptortus pedestris has a characteristic microbiota biogeography with a multispecies community in the anterior midgut and a monospecific bacterial population in the posterior midgut. We show that the posterior midgut region produces massively hundreds of specific antimicrobial peptides (AMPs), the Crypt-specific Cysteine-Rich peptides (CCRs) that have membrane-damaging antimicrobial activity against diverse bacteria but posterior midgut symbionts have elevated resistance. We determined by transposon-sequencing the genetic repertoire in the symbiont Caballeronia insecticola to manage CCR stress, identifying different independent pathways, including AMP-resistance pathways unrelated to known membrane homeostasis functions as well as cell envelope functions. Mutants in the corresponding genes have reduced capacity to colonize the posterior midgut, demonstrating that CCRs create a selective barrier and resistance is crucial in gut symbionts. Moreover, once established in the gut, the bacteria differentiate into a CCR-sensitive state, suggesting a second function of the CCR peptide arsenal in protecting the gut epithelia or mediating metabolic exchanges between the host and the gut symbionts. Our study highlights the evolution of an extreme diverse AMP family that likely contributes to establish and control the gut microbiota. | 2024 | 38865264 |
| 9376 | 9 | 0.9960 | Historical Contingency Drives Compensatory Evolution and Rare Reversal of Phage Resistance. Bacteria and lytic viruses (phages) engage in highly dynamic coevolutionary interactions over time, yet we have little idea of how transient selection by phages might shape the future evolutionary trajectories of their host populations. To explore this question, we generated genetically diverse phage-resistant mutants of the bacterium Pseudomonas syringae. We subjected the panel of mutants to prolonged experimental evolution in the absence of phages. Some populations re-evolved phage sensitivity, whereas others acquired compensatory mutations that reduced the costs of resistance without altering resistance levels. To ask whether these outcomes were driven by the initial genetic mechanisms of resistance, we next evolved independent replicates of each individual mutant in the absence of phages. We found a strong signature of historical contingency: some mutations were highly reversible across replicate populations, whereas others were highly entrenched. Through whole-genome sequencing of bacteria over time, we also found that populations with the same resistance gene acquired more parallel sets of mutations than populations with different resistance genes, suggesting that compensatory adaptation is also contingent on how resistance initially evolved. Our study identifies an evolutionary ratchet in bacteria-phage coevolution and may explain previous observations that resistance persists over time in some bacterial populations but is lost in others. We add to a growing body of work describing the key role of phages in the ecological and evolutionary dynamics of their host communities. Beyond this specific trait, our study provides a new insight into the genetic architecture of historical contingency, a crucial component of interpreting and predicting evolution. | 2022 | 35994371 |
| 9736 | 10 | 0.9960 | Coevolutionary phage training leads to greater bacterial suppression and delays the evolution of phage resistance. The evolution of antibiotic-resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria's capacity to evolve resistance may debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many suggest leveraging phages' ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that in vitro, λtrn, a phage trained for 28 d, suppressed bacteria ∼1,000-fold for three to eight times longer than its untrained ancestor. Prolonged suppression was due to a delay in the evolution of resistance caused by several factors. Mutations that confer resistance to λtrn are ∼100× less common, and while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to λtrn. Mutations that confer resistance to λtrn are more costly than mutations for untrained phage resistance. Furthermore, when resistance does evolve, λtrn is better able to suppress these forms of resistance. One way that λtrn improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This transfer of information from the host genome is an unexpected but highly efficient mode of training phage. Lastly, we found that many other independently trained λ phages were able to suppress bacterial populations, supporting the important role training could play during phage therapeutic development. | 2021 | 34083444 |
| 9237 | 11 | 0.9960 | The gossip paradox: Why do bacteria share genes? Bacteria, in contrast to eukaryotic cells, contain two types of genes: chromosomal genes that are fixed to the cell, and plasmids, smaller loops of DNA capable of being passed from one cell to another. The sharing of plasmid genes between individual bacteria and between bacterial lineages has contributed vastly to bacterial evolution, allowing specialized traits to 'jump ship' between one lineage or species and the next. The benefits of this generosity from the point of view of both recipient cell and plasmid are generally understood: plasmids receive new hosts and ride out selective sweeps across the population, recipient cells gain new traits (such as antibiotic resistance). Explaining this behavior from the point of view of donor cells is substantially more difficult. Donor cells pay a fitness cost in order to share plasmids, and run the risk of sharing advantageous genes with their competition and rendering their own lineage redundant, while seemingly receiving no benefit in return. Using both compartment based models and agent based simulations we demonstrate that 'secretive' genes which restrict horizontal gene transfer are favored over a wide range of models and parameter values, even when sharing carries no direct cost. 'Generous' chromosomal genes which are more permissive of plasmid transfer are found to have neutral fitness at best, and are generally disfavored by selection. Our findings lead to a peculiar paradox: given the obvious benefits of keeping secrets, why do bacteria share information so freely? | 2022 | 35603365 |
| 8234 | 12 | 0.9960 | Contradictory roles for antibody and complement in the interaction of Brucella abortus with its host. The ability of serum complement to kill bacteria has been linked to host resistance to Gram-negative bacteria. A mechanism for killing extracellular organisms during early invasion, following release from infected phagocytic cells, or during bacteremia would contribute to a host's ability to resist disease. In fact, the ability of serum complement to kill bacteria has been linked to disease resistance. Brucella abortus are Gram-negative intracellular pathogens. Resistance to these bacteria involves the coordinated activities of the cellular and humoral immune systems. The existence of serum-resistant forms of B. abortus has been established, and it has been shown that these bacteria can resist the killing action of complement even in the presence of specific antibody. Antibody is usually necessary for complement-mediated killing of smooth (virulent) forms of Gram-negative bacteria. An anomolous situation exists with some isolates of smooth B. abortus. Sera containing high titers of specific antibody do not support killing unless they are diluted. In the bovine, this phenomenon is associated with IgG1 and IgG2 antibodies. This finding may account for the lack of positive correlation between antibody levels and resistance to disease, which has led, perhaps wrongly, to the idea that antibody and complement are not important in resistance to brucellosis. Available evidence suggests that antibody may have contradictory roles in the interactions between a host and bacteria. Avirulent (rough) forms of the organism would be rapidly killed by complement shortly after invasion, but serum-resistant smooth forms of the organism would survive and invade resident phagocytic cells. During the process of invasion and phagocytosis, the bacteria would initiate an immune response. With time, some B. abortus organisms would be released from infected phagocytic cells. In the early stages of this process, the bacteria would encounter IgM antibody and low concentrations of IgG antibody. These would cause complement-mediated killing, and infection would be restricted to resident phagocytic cells. However, the immune response to B. abortus antigens would be intensified, and IgG antibody levels would increase. High concentrations of antibody do no support complement-mediated killing of extracellular B. abortus, but the bacteria would be opsonized by antibody and complement component fragments. This would lead to increased phagocytosis of extracellular B. abortus as they appear, and concomitant extension of disease. Because of high levels of antibody would block complement-mediated killing of B. abortus, resistance to disease at this point would be dependent on cell-mediated immunity. | 1995 | 8845060 |
| 9620 | 13 | 0.9959 | Determinants of Phage Host Range in Staphylococcus Species. Bacteria in the genus Staphylococcus are important targets for phage therapy due to their prevalence as pathogens and increasing antibiotic resistance. Here we review Staphylococcus outer surface features and specific phage resistance mechanisms that define the host range, the set of strains that an individual phage can potentially infect. Phage infection goes through five distinct phases: attachment, uptake, biosynthesis, assembly, and lysis. Adsorption inhibition, encompassing outer surface teichoic acid receptor alteration, elimination, or occlusion, limits successful phage attachment and entry. Restriction-modification systems (in particular, type I and IV systems), which target phage DNA inside the cell, serve as the major barriers to biosynthesis as well as transduction and horizontal gene transfer between clonal complexes and species. Resistance to late stages of infection occurs through mechanisms such as assembly interference, in which staphylococcal pathogenicity islands siphon away superinfecting phage proteins to package their own DNA. While genes responsible for teichoic acid biosynthesis, capsule, and restriction-modification are found in most Staphylococcus strains, a variety of other host range determinants (e.g., clustered regularly interspaced short palindromic repeats, abortive infection, and superinfection immunity) are sporadic. The fitness costs of phage resistance through teichoic acid structure alteration could make staphylococcal phage therapies promising, but host range prediction is complex because of the large number of genes involved, and the roles of many of these are unknown. In addition, little is known about the genetic determinants that contribute to host range expansion in the phages themselves. Future research must identify host range determinants, characterize resistance development during infection and treatment, and examine population-wide genetic background effects on resistance selection. | 2019 | 30902858 |
| 9833 | 14 | 0.9959 | Evolution of satellite plasmids can prolong the maintenance of newly acquired accessory genes in bacteria. Transmissible plasmids spread genes encoding antibiotic resistance and other traits to new bacterial species. Here we report that laboratory populations of Escherichia coli with a newly acquired IncQ plasmid often evolve 'satellite plasmids' with deletions of accessory genes and genes required for plasmid replication. Satellite plasmids are molecular parasites: their presence reduces the copy number of the full-length plasmid on which they rely for their continued replication. Cells with satellite plasmids gain an immediate fitness advantage from reducing burdensome expression of accessory genes. Yet, they maintain copies of these genes and the complete plasmid, which potentially enables them to benefit from and transmit the traits they encode in the future. Evolution of satellite plasmids is transient. Cells that entirely lose accessory gene function or plasmid mobility dominate in the long run. Satellite plasmids also evolve in Snodgrassella alvi colonizing the honey bee gut, suggesting that this mechanism may broadly contribute to the importance of IncQ plasmids as agents of bacterial gene transfer in nature. | 2019 | 31863068 |
| 9361 | 15 | 0.9959 | Evolutionary consequences of bacterial resistance to a flagellotropic phage. Bacteria often rapidly evolve resistance to bacteriophages (phages) by mutating or suppressing the phage-receptors, the factors that phages first target to initiate infection. Flagellotropic phages infect bacteria by initially binding to the flagellum. Since motility is an important fitness factor that allows bacteria to efficiently explore their environment, losing flagellar function to evade infection by flagellotropic phages represents a crucial trade-off. In this study, we investigated the evolutionary responses of Escherichia coli when exposed to the flagellotropic phage χ. Using an experimental evolution approach, E. coli cells were repeatedly subjected to environments rich in phage χ but selective for motility. Unlike traditional well-mixed cultures, we employed swim-plate assays to simulate spatial confinement and promote motility. Whole genome sequencing of evolved populations revealed early emergence of non-motile, χ-resistant mutants with mutations disrupting motility-related genes. Motile mutants emerged in later passages, possessing mutations in the flagellin gene fliC. Swim-plate assays showed a diverse range of motility among these mutants, with some displaying slower, and others faster, expansion speeds compared to the ancestral strain. Single-cell tracking experiments indicated an increased tumble bias in χ-resistant mutants, suggesting an adaptive response involving altered flagellar rotation. Our findings demonstrate that motility can undergo trade-offs and trade-ups with phage resistance, shedding light on the complex evolutionary dynamics between motile bacteria and flagellotropic phages. | 2025 | 40654869 |
| 9236 | 16 | 0.9959 | Mutant bacteriophages, Frank Macfarlane Burnet, and the changing nature of "genespeak" in the 1930s. In 1936, Frank Macfarlane Burnet published a paper entitled "Induced lysogenicity and the mutation of bacteriophage within lysogenic bacteria," in which he demonstrated that the introduction of a specific bacteriophage into a bacterial strain consistently and repeatedly imparted a specific property - namely the resistance to a different phage - to the bacterial strain that was originally susceptible to lysis by that second phage. Burnet's explanation for this change was that the first phage was causing a mutation in the bacterium which rendered it and its successive generations of offspring resistant to lysogenicity. At the time, this idea was a novel one that needed compelling evidence to be accepted. While it is difficult for us today to conceive of mutations and genes outside the context of DNA as the physico-chemical basis of genes, in the mid 1930s, when this paper was published, DNA's role as the carrier of hereditary information had not yet been discovered and genes and mutations were yet to acquire physical and chemical forms. Also, during that time genes were considered to exist only in organisms capable of sexual modes of replication and the status of bacteria and viruses as organisms capable of containing genes and manifesting mutations was still in question. Burnet's paper counts among those pieces of work that helped dispel the notion that genes, inheritance and mutations were tied to an organism's sexual status. In this paper, I analyze the implications of Burnet's paper for the understanding of various concepts - such as "mutation," and "gene," - at the time it was published, and how those understandings shaped the development of the meanings of these terms and our modern conceptions thereof. | 2010 | 20665082 |
| 569 | 17 | 0.9959 | DNA mismatch repair and cancer. Mutations in DNA mismatch repair (MMR) genes have been associated with hereditary nonpolyposis colorectal cancer. Studies in bacteria, yeast and mammals suggest that the basic components of the MMR system are evolutionarily conserved, but studies in eukaryotes also imply novel functions for MMR proteins. Recent results suggest that mutations in MMR genes lead to tumorigenesis in mice, but DNA replication errors appear to be insufficient to initiate intestinal tumorigenesis in this model system. Additionally, MMR-deficient cell lines display a mutator phenotype and resistance to several cytotoxic agents, including compounds widely used in cancer chemotherapy. | 1998 | 9640530 |
| 8260 | 18 | 0.9958 | Pseudotyping Bacteriophage P2 Tail Fibers to Extend the Host Range for Biomedical Applications. Bacteriophages (phages) represent powerful potential treatments against antibiotic-resistant bacterial infections. Antibiotic-resistant bacteria represent a significant threat to global health, with an estimated 70% of infection-causing bacteria being resistant to one or more antibiotics. Developing novel antibiotics against the limited number of cellular targets is expensive and time-consuming, and bacteria can rapidly develop resistance. While bacterial resistance to phage can evolve, bacterial resistance to phage does not appear to spread through lateral gene transfer, and phage may similarly adapt through mutation to recover infectivity. Phages have been identified for all known bacteria, allowing the strain-selective killing of pathogenic bacteria. Here, we re-engineered the Escherichia coli phage P2 to alter its tropism toward pathogenic bacteria. Chimeric tail fibers formed between P2 and S16 genes were designed and generated through two approaches: homology- and literature-based. By presenting chimeric P2:S16 fibers on the P2 particle, our data suggests that the resultant phages were effectively detargeted from the native P2 cellular target, lipopolysaccharide, and were instead able to infect via the proteinaceous receptor, OmpC, the natural S16 receptor. Our work provides evidence that pseudotyping P2 is feasible and can be used to extend the host range of P2 to alternative receptors. Extension of this work could produce alternative chimeric tail fibers to target pathogenic bacterial threats. Our engineering of P2 allows adsorption through a heterologous outer-membrane protein without culturing in its native host, thus providing a potential means of engineering designer phages against pathogenic bacteria from knowledge of their surface proteome. | 2022 | 36084285 |
| 8291 | 19 | 0.9958 | Pseudomonas Can Survive Tailocin Killing via Persistence-Like and Heterogenous Resistance Mechanisms. Phage tail-like bacteriocins (tailocins) are bacterially produced protein toxins that mediate competitive interactions between cocolonizing bacteria. Both theoretical and experimental research has shown there are intransitive interactions between bacteriocin-producing, bacteriocin-sensitive, and bacteriocin-resistant populations, whereby producers outcompete sensitive cells, sensitive cells outcompete resistant cells, and resistant cells outcompete producers. These so-called rock-paper-scissors dynamics explain how all three populations occupy the same environment, without one driving the others extinct. Using Pseudomonas syringae as a model, we demonstrate that otherwise sensitive cells survive bacteriocin exposure through a physiological mechanism. This mechanism allows cells to survive bacteriocin killing without acquiring resistance. We show that a significant fraction of the target cells that survive a lethal dose of tailocin did not exhibit any detectable increase in survival during a subsequent exposure. Tailocin persister cells were more prevalent in stationary- rather than log-phase cultures. Of the fraction of cells that gained detectable resistance, there was a range from complete (insensitive) to incomplete (partially sensitive) resistance. By using genomic sequencing and genetic engineering, we showed that a mutation in a hypothetical gene containing 8 to 10 transmembrane domains causes tailocin high persistence and that genes of various glycosyltransferases cause incomplete and complete tailocin resistance. Importantly, of the several classes of mutations, only those causing complete tailocin resistance compromised host fitness. This result indicates that bacteria likely utilize persistence to survive bacteriocin-mediated killing without suffering the costs associated with resistance. This research provides important insight into how bacteria can escape the trap of fitness trade-offs associated with gaining de novo tailocin resistance.IMPORTANCE Bacteriocins are bacterially produced protein toxins that are proposed as antibiotic alternatives. However, a deeper understanding of the responses of target bacteria to bacteriocin exposure is lacking. Here, we show that target cells of Pseudomonas syringae survive lethal bacteriocin exposure through both physiological persistence and genetic resistance mechanisms. Cells that are not growing rapidly rely primarily on persistence, whereas those growing rapidly are more likely to survive via resistance. We identified various mutations in lipopolysaccharide biogenesis-related regions involved in tailocin persistence and resistance. By assessing host fitness of various classes of mutants, we showed that persistence and subtle resistance are mechanisms P. syringae uses to survive competition and preserve host fitness. These results have important implications for developing bacteriocins as alternative therapeutic agents. | 2020 | 32312747 |