This can lead to strains with multiple drug resistance, which are more difficult to eliminate due to limited effective treatment options. Image: A normal bacterial genome results in normal cellular structure and function whereas a mutation in the bacterial genome results in altered cellular structure and function and ultimately modified susceptibility.
Any change in a single base pair may lead to a corresponding change in one or more of the corresponding amino acids, which can then change the enzyme or cell structure and consequently affect the affinity or effectiveness activity of related antimicrobials. In prokaryotic genomes, mutations frequently occur due to base changes caused by exogenous agents, DNA polymerase errors, deletions, insertions, and duplications Gillespie, Horizontal gene transfer, or the process of swapping genetic material between neighboring bacteria, is another means by which resistance can be acquired.
Many of the antibiotic resistance genes are carried on plasmids, transposons, or integrons that act as vectors to transfer genes to other similar bacterial species. Horizontal gene transfer may occur via three main mechanisms: transformation, transduction, or conjugation.
Transformation involves the process in which bacteria uptake short fragments of DNA. Transduction involves transfer of DNA from one bacterium into another via bacteriophages.
Conjugation involves transfer of DNA via sex pilus and requires cell-to-cell contact. Watch a short video about horizontal gene transfer. Did You Know? Conjugation was first described in by Lederberg and Tatum, based on studies showing that the intestinal bacteria E. Torrence and Isaacson, Historically, veterinary practitioners prescribed antibiotics based on expected mode of action, spectrum of activity, and clinical experience.
With the emergence and spread of antimicrobial resistance, treatment of bacterial infections has become increasingly difficult and is no longer as straightforward as it was many years prior.
Practitioners now need to consider that the organisms being treated may be resistant to some or all antimicrobial agents. These considerations require antimicrobial susceptibility testing as a standard procedure. Antimicrobial susceptibility testing methods are in vitro procedures used to detect antimicrobial resistance and susceptibility in individual bacterial isolates to a wide array of antimicrobial therapy options.
These same methods can also be used for monitoring the emergence and spread of resistant microorganisms in the population.
Clinical breakpoints are threshold values established for each pathogen-antibiotic-host combination indicating at what level of antibiotic the isolate is sensitive, intermediate, or resistant to standard manufacturer-recommended treatment regimens. The interpretative criteria for these are based on extensive studies that correlate laboratory resistance data with serum-achievable levels for each antimicrobial agent and a history of successful and unsuccessful therapeutic outcomes.
Although veterinary laboratories originally based interpretations on standards established using human pathogens, it became apparent by the early s that such an approach did not reliably predict clinical outcomes when applied to veterinary practice. Subsequently, groups were established to develop veterinary-specific standards. Most often, interpretation is reduced to whether the isolate is classified as susceptible, intermediately susceptible, or resistant to a particular antibiotic.
It should, however, be remembered that these in vitro procedures are only approximations of in vivo conditions, which can be very different depending on the nature of the drug, the nature of the host, and the conditions surrounding the interaction between the antibiotic and the target pathogen. One critical aspect is following standardized, quality-controlled procedures that can generate reproducible results. Because of the required culture time, antimicrobial susceptibility testing by the above methods may take several days, which is not ideal, particularly in critical clinical cases demanding urgency.
Often practitioners may use locally established antibiograms as a guideline for therapy. An antibiogram is a compiled susceptibility report or table of commonly isolated organisms in a particular hospital, farm, or geographic area, which can serve as a useful guideline in therapy before actual culture and susceptibility data becomes available for reference.
In some cases, specific resistance gene detection by PCR or direct enzyme testing can provide earlier susceptibility information Example: mecA detection in methicillin-resistant staphylococci. To learn more, read About Antibiograms. There are several antimicrobial susceptibility testing methods available today and each one has its respective advantages and disadvantages. They all have the same goal, which is to provide a reliable prediction of whether an infection caused by a bacterial isolate will respond therapeutically to a particular antibiotic treatment.
These data may be used as guidelines for treatment, or as indicators of emergence and spread of resistance on a population level based on passive or active surveillance. Some examples of antibiotic susceptibility testing methods are:. Selection of the appropriate method will depend on the intended degree of accuracy, convenience, urgency, availability of resources, availability of technical expertise, and cost.
Interpretation should be based on veterinary standards whenever possible rather than on human medical standards due to applicability. Among these available tests, the two most commonly used methods in veterinary laboratories are the agar disk-diffusion method and the broth microdilution method.
The broth dilution method involves placing the isolate into several separate broth solutions containing an antimicrobial agent in a series of varying concentrations. Microdilution testing uses about 0. Of the ARGs, 80 are present in one or more strains from each niche, 7 are shared by pathogens and environmental strains only, 2 are shared by pathogens and symbiotic strains, and one is shared by environmental and symbiotic strains.
Diagram showing the Serratia spp. Pathogens red , environmental blue , and symbiotic green. The polymyxin resistance operon and the genes catA, bacA, fosA and hslJ , which confer resistance to chloramphenicol, bacitracin, fosfomycin and novobiocin, respectively, are among the shared ARGs.
Most of the strains share most of the genes associated with efflux systems. The 14 ARGs exclusive of environmental strains are genes found on the chromosome, all of intrinsic resistance except for the vancomycin resistance gene vanW found on a transposon.
Only one ARG was found to be exclusive of a symbiotic strain, an allele of the efflux pump AcrF that confers resistance to ciprofloxacin. Five efflux pumps genes, mexP, mexQ, opmE and triC , from the RND family conferring resistance to macrolides, fluoroquinolones and triclosan, respectively, and the gene mdsC , which is part of the efflux pump MdsAB absent in this sample , are shared by pathogen and environmental strains.
Only the streptogramin efflux pump gene, vgaC , is shared by environmental and symbiotic strains and is absent in pathogens. A PCoA analysis was performed to visualize the similarities of the Serratia spp. The environmental strains were sub-divided into strains associated with soil and plants, strains isolated from water and strains isolated from food. The plot of Euclidean distances shows that the resistomes of nosocomial and pathogenic strains are similar to those isolated from the natural environment based on the number of ARGs Figure 8.
The most dissimilar resistome was from the co-obligate aphid symbiont, followed by the resistome of strain Serratia sp. ATCC isolated from salt marsh water and a questionable member of the genus Serratia , the resistome of the fungus garden symbiont Serratia sp. FGI94 reclassified in this work as S.
Nosocomial strains with the highest number of acquired ARGs, S. It is not surprising that nosocomial strains present the highest number of acquired ARGs as they are subject to a strong selection pressure due to frequent antibiotic use in hospitals. Principal Coordinate Analysis PCoA plot depicting Euclidean distances between resistomes of nosocomial strains red , animal pathogens orange , environmental associated with soil and plants green , environmental isolated from water blue , environmental isolated from food purple , and environmental symbiotic bacteria yellow calculated using ARGs counts.
It would be interesting to include a new set of Serratia isolates to be collected from animal and environment sources that could confirm the selection pressure of the indiscriminate use of antibiotics in the hospital environment on nosocomial strains and address unsolved issues on the zoonotic origin of antimicrobial resistance genes Cloeckaert et al. The microbial pan-genome is the cumulative number of different genes found within genomes of a particular taxonomic rank, usually within a species, though this can be extended to higher levels, such as a genus Tettelin et al.
It contains the core genes, common to all strains of the study, the accessory genome containing genes present between two and n —1 strains, and the unique or singleton genes present only in a single strain. Inside the pan-genome, we can study different features, such as the resistome Rouli et al. The pan-genome size, and whether it is open or closed, depends in part on bacterial lifestyle. Large and open pan-genomes are associated with bacterial species that live within communities and that are prone to horizontal gene exchange.
However, the more genomes used to predict the pan-genome, the larger its predicted size, due to the contribution of rare genes Tettelin et al. Here, we report an observed pan-genome of 12, clusters of genes for a collection of 32 strains of the genus Serratia , which we consider a relatively large pan-genome based on the small sample size of this genus. It is also considered to be relatively large when compared to the pan-genome of 5, clusters for 50 Streptococcus genomes from 14 species Contreras-Moreira and Vinuesa, , and around 10, family genes for the Salmonella genus Jacobsen et al.
On the other hand, for the genus Vibrio , there is a report of a pan-genome consisting of 26, genes for 43 different species Thompson et al. For the small genome of genus Mycoplasma there is an estimate of a pan-genome consisting of 8, genes, which is very large if we consider the small genome size 0. Large pan-genomes indicate that these genomes have a considerable amount of unique sequences, such as mobile elements, genomic islands, transposons or prophages.
The phylogenetic analysis based on the pan-genome of the 32 Serratia spp. All S. SCB1, suggesting that they should be reclassified as members of the S. It is worth noting that S. SCB1, which are both insect pathogens. This fact can be explained due to the dual quality of S. Two of the S. This grouping is congruent with previous studies Abebe-Akele et al. Serratia sp.
FGI94, which is a fungus symbiont strain and S. The most distantly related strains are C. ATCC isolated from water and the co-obligate aphid symbiont S. Bacterial antimicrobial resistance occurs by one or a combination of different mechanisms: a reduction in antibiotic passage through the bacterial outer membrane preventing access to the target; modification of antibiotic targets by modifying enzymes; antibiotic hydrolysis; and increased transport of the antibiotic out of the cell by efflux pumps Shaikh et al.
The modulation of resistance to certain antibiotics depends also on the activation of regulatory genes, mutations of specific genes, intrinsic differences in the structure of the outer membrane, such as porin alterations that reduce the entry of antimicrobials, such as carbapenems Gupta et al. It is important to recognize that the concept of antimicrobial resistance is a phenomenon with many layers of complexity. In this comparative study, we looked for all classes of genes involved in the different antibiotic resistance mechanisms mentioned above, including regulatory genes detailed information is shown in Supplementary Table S2.
The resistome of Serratia spp. These pumps, besides conferring resistance to antibiotics, have other important physiological roles and therefore, have greater clinical relevance than is usually attributed to them Piddock, This resistance to a wide spectrum of antimicrobials makes it difficult to select an appropriate treatment for Serratia spp.
Surprisingly, the Serratia genus lacks resistance genes for trimethoprim and sulfonamides with the exception of S. One evolutionary hypothesis for the lack of these resistance genes in this genus could be based on the antibiotic resistance cost. Resistance is often associated with reduced bacterial fitness and the reduction in antibiotic use will benefit the fitter susceptible bacteria Andersson and Hughes, The combination of these antimicrobials has been suspended in many countries relaxing the selection pressure on these genes and leading to gene loss.
An alternative hypothesis could be that this genus is intrinsically susceptible to trimethoprim-sulfamethoxazole and that they have never carried these genes on their chromosomes.
The presence of these ARGs on the plasmids of two nosocomial S. Our results show that most of the resistomes of pathogenic and environmental bacteria of the genus Serratia are very similar in the number of ARGs shared, being the content of horizontally transferred genes what determine the differences with the nosocomial strains.
To date there are around S. This can lead to a potential limitation of our results; nevertheless, we presume that the results obtained here are a suitable approximation for the resistome of this bacterial genus. The nosocomial strains with the highest number of acquired ARGs are S. While ARGs of environmental isolates may originally have had different functions aside from conferring resistance to antibiotics produced by other competing bacteria, these genes have now been acquired as resistance genes in pathogenic bacteria via HGT Berglund, There are several other known factors that promote resistance in susceptible bacteria: selection pressure placed on susceptible microbes through the use of therapeutic agents, over-prescription, self-medication, treatment non-compliance, use of antibiotics in food-producing animals and in agriculture in general Knobler, , and an increase in antimicrobial residues found in the environment, most particularly in water Harris et al.
It is important to raise awareness concerning the excessive use of antibiotics in agricultural, poultry and livestock industries by creating specialized surveillance institutions that coordinate the health, food and environmental sectors, enabling the identification of the many routes for both dissemination and acquisition of ARGs from agricultural and environmental microbial communities to human pathogens, preventing nosocomial outbreaks.
It is also crucial to identify the intrinsic resistance profile of a given microorganism or species in order to select the most suitable antimicrobial treatment not forgetting to link the laboratory-based phenotype antibiogram to the genomic data to understand which ARGs are in circulation and which represent a threat to the medical community McArthur and Wright, Due to the fact that the Serratia species have a high number of efflux systems, no matter how many times a new antibiotic molecule is generated, resistance will persist.
Therefore, new strategies for generating effective treatments have to take into account other targets, for example, inhibiting the expression of regulatory genes of the efflux pumps. Whole genome sequencing and metagenomics are opening the door to rapid genotype-based resistance diagnosis Bertelli and Greub, ; Wyrsch et al. Awareness of the increasing problem related to antibiotic resistance has been a great concern in public health in recent years. Combating this problem requires an understanding of the mechanisms, evolution and spread of ARGs and the manufacture of new drugs that can circumvent resistance.
Members of the Serratia genus are gram-negative bacteria of the Enterobacteriacea family that have been isolated from various ecological niches, such as soil, water and hospitals.
This makes it difficult to choose suitable treatments. Knowing the genomic composition of Serratia spp.
LS-M performed the experiments, did the phylogenetic analysis, analyzed the data, and wrote the paper. PV performed the bioinformatic analysis.
AC the final approval of the version of the manuscript to be published. RM-E conceived and designed the experiments, contributed in writing the paper, and gave the final approval for the publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The colors in the heat map represent pairwise ANI values, with a gradient from light yellow high identity to red low identity. Genes found on the chromosome in white color, genes found on plasmids in orange color, genes found on transposons in blue color, genes found on probable genomic islands in purple color, regulatory genes in pink color and genes with mutations that confer resistance in green color.
Abebe-Akele, F. Genome sequence and comparative analysis of a putative entomopathogenic Serratia isolated from Caenorhabditis briggsae. BMC Genomics Aendekerk, S. The MexGHI-OpmD multidrug efflux pump controls growth, antibiotic susceptibility and virulence in Pseudomonas aeruginosa via 4-quinolone-dependent cell-to-cell communication.
Microbiology , — Aldema, M. Purification of the Tnspecified tetracycline efflux antiporter TetA in a native state as a polyhistidine fusion protein. Allen, H. ISME J. Altschul, S.
Basic local alignment search tool. Andersson, D. Antibiotic resistance and its costs: it is possible to reverse resistance? Begic, S. Characterization of the Serratia marcescens SdeCDE multidrug efflux pump studied via gene knockout mutagenesis. Berglund, B. Environmental dissemination of antibiotic resistance genes and correlation to anthropogenic contamination with antibiotics.
Bernard, R. BcrC from Bacillus subtilis acts as an undecaprenyl pyrophosphate phosphatase in bacitracin resistance. Bertelli, C. Rapid bacterial genome sequencing: methods and applications in clinical microbiology.
IslandViewer 4: expanded prediction of genomic islands for larger-scale datasets. Nucleic Acids Res. Bertrand, X. Antimicrobial susceptibility among Gram-negative isolates collected from Intensive Care Units in North America, Europe, the Asia-Pacific Rim, Latin America, the Middle East, and Africa between and as part of the tigecycline evaluation and surveillance trial.
Blair, J. Molecular mechanisms of antibiotic resistance. Advanced Search. Sign In. Skip Nav Destination Article Navigation. Close mobile search navigation Article navigation. Volume 61, Issue 1. Issue Editors. Henrietta Venter Henrietta Venter.
This Site. Google Scholar. Previous Article Next Article. All Issues. Cover Image Cover Image. Basu, J. Identification and overexpression in Escherichia coli of a Mycobacterium leprae gene, pon1, encoding a high-molecular-mass class A penicillin-binding protein. Becker, B. Aminoglycoside antibiotics in the 21st century. ACS Chem.
Bengtsson-Palme, J. Environmental factors influencing the development and spread of antibiotic resistance. Benveniste, R. Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria.
Bhullar, K. Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS One 7:e Billot-Klein, D. Association constants for the binding of vancomycin and teicoplanin to N-acetyl-D-alanyl-D-alanine and N-acetyl-D-alanyl-D-serine. Binda, E. ATCC FEBS J. Old and new glycopeptide antibiotics: action and resistance. Antibiotics Basel 3, — Bismuth, R. Gene heterogeneity for tetracycline resistance in Staphylococcus spp.
Blair, J. Molecular mechanisms of antibiotic resistance. Blanco, M. Resistance in inhibitors of RNA polymerase in actinomycetes which produce them. Blazquez, J. Antimicrobials as promoters of genetic variation. Brisson-Noel, A. Evidence for natural gene transfer from gram-positive cocci to Escherichia coli. Brown, K.
Role of aromatic and negatively charged residues of DrrB in multisubstrate specificity conferred by the DrrAB system of Streptomyces peucetius. Biochemistry 56, — Bugg, T. Molecular basis for vancomycin resistance in Enterococcus faecium BM biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA. Biochemistry 30, — Burdett, V. Tet M -promoted release of tetracycline from ribosomes is GTP dependent.
Buriankova, K. Molecular basis of intrinsic macrolide resistance in the Mycobacterium tuberculosis complex. Calcutt, M.
Cloning of a lincosamide resistance determinant from Streptomyces caelestis , the producer of celesticetin, and characterization of the resistance mechanism. Canton, R. The CTX-M beta-lactamase pandemic. Carattoli, A. Plasmids and the spread of resistance. Chang, H. Origin and proliferation of multiple-drug resistance in bacterial pathogens. Chen, J. Phage-mediated intergeneric transfer of toxin genes. Science , — Chufan, E. Molecular basis of the polyspecificity of P-glycoprotein ABCB1 : recent biochemical and structural studies.
Cancer Res. Claverys, J. Induction of competence regulons as a general response to stress in gram-positive bacteria. Colomer-Lluch, M. Antibiotic resistance genes in bacterial and bacteriophage fractions of Tunisian and Spanish wastewaters as markers to compare the antibiotic resistance patterns in each population. Coque, J. Genes for a beta-lactamase, a penicillin-binding protein and a transmembrane protein are clustered with the cephamycin biosynthetic genes in Nocardia lactamdurans.
EMBO J. Coughlin, J. BlmB and TlmB provide resistance to the bleomycin family of antitumor antibiotics by N-acetylating metal-free bleomycin, tallysomycin, phleomycin, and zorbamycin. Biochemistry 53, — Cox, G. Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions. Dantas, G. Context matters — The complex interplay between resistome genotypes and resistance phenotypes. Davies, J. Origins and evolution of antibiotic resistance. Bacterial resistance to aminoglycoside antibiotics.
Trends Microbiol. Antibiotic resistance is ancient. Nature , — Sampling the antibiotic resistome. Doi, Y. Domingues, S. Integrons: vehicles and pathways for horizontal dissemination in bacteria. Elements 2, — Douthwaite, S. Doyle, D. Characterization of an oxytetracycline-resistance gene, otrA, of Streptomyces rimosus.
Du, L. The biosynthetic gene cluster for the antitumor drug bleomycin from Streptomyces verticillus ATCC supporting functional interactions between nonribosomal peptide synthetases and a polyketide synthase.
Dubey, R. Daunorubicin forms a specific complex with a secreted serine protease of Streptomyces peucetius. World J. Fajardo, A. The neglected intrinsic resistome of bacterial pathogens.
PLoS One 3:e Fishovitz, J. Penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus. Floss, H. Rifamycin-mode of action, resistance, and biosynthesis. Fong, D. Crystal structures of two aminoglycoside kinases bound with a eukaryotic protein kinase inhibitor. PLoS One 6:e Forsberg, K.
The shared antibiotic resistome of soil bacteria and human pathogens. Forsman, M. Molecular analysis of beta-lactamases from four species of Streptomyces : comparison of amino acid sequences with those of other beta-lactamases. Frasch, H. Alternative pathway to a glycopeptide-resistant cell wall in the balhimycin producer Amycolatopsis balhimycina. ACS Infect. Fyfe, C. Resistance to macrolide antibiotics in public health pathogens.
Cold Spring Harb. Galimand, M. RNA 17, — Galm, U. The biosynthetic gene cluster of zorbamycin, a member of the bleomycin family of antitumor antibiotics, from Streptomyces flavoviridis ATCC Gatignol, A.
Bleomycin resistance conferred by a drug-binding protein. FEBS Lett. Gillings, M. Integrons: past, present, and future. Goerke, C. Ciprofloxacin and trimethoprim cause phage induction and virulence modulation in Staphylococcus aureus. Guilfoile, P. A bacterial analog of the mdr gene of mammalian tumor cells is present in Streptomyces peucetius , the producer of daunorubicin and doxorubicin. Gullberg, E. Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals.
MBio 5:e Selection of resistant bacteria at very low antibiotic concentrations. Haaber, J. Bacterial viruses enable their host to acquire antibiotic resistance genes from neighbouring cells. Transfer of antibiotic resistance in Staphylococcus aureus.
Heinzel, P. Relationships between antibiotic and protein kinases. Hoffman-Roberts, H. Investigational new drugs for the treatment of resistant pneumococcal infections. Expert Opin. Drugs 14, — Hong, H. The role of the novel fem protein VanK in vancomycin resistance in Streptomyces coelicolor. Characterization of an inducible vancomycin resistance system in Streptomyces coelicolor reveals a novel gene vanK required for drug resistance.
Hooper, D. Fluoroquinolone resistance among Gram-positive cocci. Lancet Infect. Hopwood, D. Google Scholar. Hu, Y. The antibiotic resistome: gene flow in environments, animals and human beings.
Huddleston, J. Horizontal gene transfer in the human gastrointestinal tract: potential spread of antibiotic resistance genes. Drug Resist.
Humeniuk, C. Huovinen, P. Resistance to trimethoprim-sulfamethoxazole. Ishida, K. Characterization of pbpA and pbp2 encoding penicillin-binding proteins located on the downstream of clavulanic acid gene cluster in Streptomyces clavuligerus.
Jacoby, G. AmpC beta-lactamases. Jiang, X. Dissemination of antibiotic resistance genes from antibiotic producers to pathogens. Johnston, C. Bacterial transformation: distribution, shared mechanisms and divergent control. Karuppasamy, K. Partial loss of self-resistance to daunorubicin in drrD mutant of Streptomyces peucetius.
Kashuba, E. Ancient permafrost staphylococci carry antibiotic resistance genes. Health Dis. Kaur, P. Biochemical characterization of domains in the membrane subunit DrrB that interact with the ABC subunit DrrA: identification of a conserved motif. Biochemistry 44, — Kenzaka, T. High-frequency phage-mediated gene transfer in freshwater environments determined at single-cell level.
King, D. One ring to rule them all: current trends in combating bacterial resistance to the beta-lactams. Protein Sci. Klumper, U.
Broad host range plasmids can invade an unexpectedly diverse fraction of a soil bacterial community. Knapp, C. Evidence of increasing antibiotic resistance gene abundances in archived soils since Kojic, M.
Cloning and characterization of an aminoglycoside resistance determinant from Micromonospora zionensis. Kumagai, T. Characterization of the bleomycin resistance determinant encoded on the transposon Tn5. Larranaga, O. Phage particles harboring antibiotic resistance genes in fresh-cut vegetables and agricultural soil. Larsson, D. Pollution from drug manufacturing: review and perspectives. B Biol. Laskaris, P.
Coevolution of antibiotic production and counter-resistance in soil bacteria. Lee, A. Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistance. Lee, Y. Phage conversion for beta-lactam antibiotic resistance of Staphylococcus aureus from Foods. Lessard, I.
0コメント