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Antibiotic Resistance: Appearance, Evolution, and Spread

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 40783

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Dr. Baltasar Mayo

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Departamento de Microbiología y Bioquímica, Instituto de Productos Lácteos de Asturias (IPLA), Consejo Superior de Investigaciones Científicas (CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain
Interests: physiology and genetics of lactic acid bacteria and bifidobacteria (LAB&B); dairy starters; probiotics; molecular ecology of dairy products and human gastrointestinal tract; plasmids and vectors for LAB&B; antibiotic resistance in LAB&B
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Dr. Ana Belén Flórez

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Departamento de Microbiología y Bioquímica, Instituto de Productos Lácteos de Asturias (IPLA), Consejo Superior de Investigaciones Científicas (CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain
Interests: food safety and quality; molecular ecology of dairy products; genome analysis and functional characterization of lactic acid bacteria (LAB); dairy starters; phenotypic and molecular analysis of antibiotic resistance in LAB
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The containment of the development and spread of antibiotic resistance is nowadays one of the major worldwide challenges for the maintenance of human health. If a continuous increase in antibiotic resistance occurs, public health services are expected to enter into the so-called postantibiotic era in a few decades, a situation similar to the one before the discovery of antibiotics. For years, most studies on antibiotic resistance have focused on clinical settings, while antibiotic resistance and transfer have been broadly seen everywhere in the environment. Therefore, studies on this topic have to be broadened to all environmental-, animal-, and human-associated ecosystems.

Understanding the molecular mechanisms involved in the promotion, evolution, distribution, and dissemination of antibiotic resistance in different niches is pivotal, as this might help to obtain scientific knowledge to fight against the appearance and/or spread of resistance. Therefore, we invite authors to submit articles to this Special Issue that will include new and updated principles on these matters from a multihierarchical viewpoint encompassing studies on ecology, molecular biology, and genetics of resistant populations, resistant bacteria, mobile genetic elements, and resistance transfer mechanisms. The integration of data from the application of multiomic approaches, such as genomics, transcriptomics, metagenomics, metatranscriptomics, etc, are of great relevance. However, pure clinical studies are not suitable for this issue, but clinical submissions with molecular experiments are welcomed.

Dr. Baltasar Mayo
Dr. Ana Belén Flórez
Guest Editors

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Keywords

antibiotic resistance
antimicrobial resistance
acquired resistance
cut-off values
resistant bacteria
resistome
resistance mechanisms
multidrug resistance
mobile genetic elements
horizontal gene transfer
resistance transfer
resistance dispersion modeling
omics approaches
biocide coresistance
resistance biological cost
and resistance risk

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Published Papers (10 papers)

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Research

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17 pages, 2169 KiB

Open AccessArticle

Directed Recovery and Molecular Characterization of Antibiotic Resistance Plasmids from Cheese Bacteria

by Ana Belén Flórez, Lucía Vázquez, Javier Rodríguez and Baltasar Mayo

Int. J. Mol. Sci. 2021, 22(15), 7801; https://doi.org/10.3390/ijms22157801 - 21 Jul 2021

Cited by 7 | Viewed by 3482

Abstract

Resistance to antimicrobials is a growing problem of worldwide concern. Plasmids are thought to be major drivers of antibiotic resistance spread. The present work reports a simple way to recover replicative plasmids conferring antibiotic resistance from the bacteria in cheese. Purified plasmid DNA from colonies grown in the presence of tetracycline and erythromycin was introduced into plasmid-free strains of Lactococcus lactis, Lactiplantibacillus plantarum and Lacticaseibacillus casei. Following antibiotic selection, the plasmids from resistant transformants were isolated, analyzed by restriction enzyme digestion, and sequenced. Seven patterns were obtained for the tetracycline-resistant colonies, five from L. lactis, and one each from the lactobacilli strains, as well as a single digestion profile for the erythromycin-resistant transformants obtained in L. lactis. Sequence analysis respectively identified tet(S) and ermB in the tetracycline- and erythromycin-resistance plasmids from L. lactis. No dedicated resistance genes were detected in plasmids conferring tetracycline resistance to L. casei and L. plantarum. The present results highlight the usefulness of the proposed methodology for isolating functional plasmids that confer antibiotic resistance to LAB species, widen our knowledge of antibiotic resistance in the bacteria that inhabit cheese, and emphasize the leading role of plasmids in the spread of resistance genes via the food chain. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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24 pages, 431 KiB

Open AccessArticle

Presence of β-Lactamase-producing Enterobacterales and Salmonella Isolates in Marine Mammals

by Olivia M. Grünzweil, Lauren Palmer, Adriana Cabal, Michael P. Szostak, Werner Ruppitsch, Christian Kornschober, Maciej Korus, Dusan Misic, Tanja Bernreiter-Hofer, Anna D. J. Korath, Andrea T. Feßler, Franz Allerberger, Stefan Schwarz, Joachim Spergser, Elke Müller, Sascha D. Braun, Stefan Monecke, Ralf Ehricht, Chris Walzer, Hrvoje Smodlaka and Igor Loncaric Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(11), 5905; https://doi.org/10.3390/ijms22115905 - 31 May 2021

Cited by 13 | Viewed by 4385

Abstract

Marine mammals have been described as sentinels of the health of marine ecosystems. Therefore, the aim of this study was to investigate (i) the presence of extended-spectrum β-lactamase (ESBL)- and AmpC-producing Enterobacterales, which comprise several bacterial families important to the healthcare sector, as well as (ii) the presence of Salmonella in these coastal animals. The antimicrobial resistance pheno- and genotypes, as well as biocide susceptibility of Enterobacterales isolated from stranded marine mammals, were determined prior to their rehabilitation. All E. coli isolates (n = 27) were screened for virulence genes via DNA-based microarray, and twelve selected E. coli isolates were analyzed by whole-genome sequencing. Seventy-one percent of the Enterobacterales isolates exhibited a multidrug-resistant (MDR) pheno- and genotype. The gene bla_CMY (n = 51) was the predominant β-lactamase gene. In addition, bla_TEM-1 (n = 38), bla_SHV-33 (n = 8), bla_CTX-M-15 (n = 7), bla_OXA-1 (n = 7), bla_SHV-11 (n = 3), and bla_DHA-1 (n = 2) were detected. The most prevalent non-β-lactamase genes were sul2 (n = 38), strA (n = 34), strB (n = 34), and tet(A) (n = 34). Escherichia coli isolates belonging to the pandemic sequence types (STs) ST38, ST167, and ST648 were identified. Among Salmonella isolates (n = 18), S. Havana was the most prevalent serotype. The present study revealed a high prevalence of MDR bacteria and the presence of pandemic high-risk clones, both of which are indicators of anthropogenic antimicrobial pollution, in marine mammals. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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14 pages, 1687 KiB

Open AccessArticle

Molecular and Functional Characterization of MobK Protein—A Novel-Type Relaxase Involved in Mobilization for Conjugational Transfer of Klebsiella pneumoniae Plasmid pIGRK

by Katarzyna Paulina Nowak, Agnieszka Sobolewska-Ruta, Agata Jagiełło, Anna Bierczyńska-Krzysik, Piotr Kierył and Paweł Wawrzyniak

Int. J. Mol. Sci. 2021, 22(10), 5152; https://doi.org/10.3390/ijms22105152 - 13 May 2021

Cited by 2 | Viewed by 3234

Abstract

Conjugation, besides transformation and transduction, is one of the main mechanisms of horizontal transmission of genetic information among bacteria. Conjugational transfer, due to its essential role in shaping bacterial genomes and spreading of antibiotics resistance genes, has been widely studied for more than 70 years. However, new and intriguing facts concerning the molecular basis of this process are still being revealed. Most recently, a novel family of conjugative relaxases (Mob proteins) was distinguished. The characteristic feature of these proteins is that they are not related to any of Mobs described so far. Instead of this, they share significant similarity to tyrosine recombinases. In this study MobK—a tyrosine recombinase-like Mob protein, encoded by pIGRK cryptic plasmid from the Klebsiella pneumoniae clinical strain, was characterized. This study revealed that MobK is a site-specific nuclease and its relaxase activity is dependent on both a conserved catalytic tyrosine residue (Y¹⁷⁹) that is characteristic of tyrosine recombinases and the presence of Mg²⁺ divalent cations. The pIGRK minimal origin of transfer sequence (oriT) was also characterized. This is one of the first reports presenting tyrosine recombinase-like conjugative relaxase protein. It also demonstrates that MobK is a convenient model for studying this new protein family. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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18 pages, 2059 KiB

Open AccessArticle

The Lactococcal dgkB (yecE) and dxsA Genes for Lipid Metabolism Are Involved in the Resistance to Cell Envelope-Acting Antimicrobials

by Aleksandra Tymoszewska and Tamara Aleksandrzak-Piekarczyk

Int. J. Mol. Sci. 2021, 22(3), 1014; https://doi.org/10.3390/ijms22031014 - 20 Jan 2021

Cited by 7 | Viewed by 2658

Abstract

The emergence of antibiotic-resistant bacteria led to an urgent need for next-generation antimicrobial agents with novel mechanisms of action. The use of positively charged antimicrobial peptides that target cytoplasmic membrane is an especially promising strategy since essential functions and the conserved structure of the membrane hinder the development of bacterial resistance. Aureocin A53- and enterocin L50-like bacteriocins are highly cationic, membrane-targeting antimicrobial peptides that have potential as next-generation antibiotics. However, the mechanisms of resistance to these bacteriocins and cross-resistance against antibiotics must be examined before application to ensure their safe use. Here, in the model bacterium Lactococcus lactis, we studied the development of resistance to selected aureocin A53- and enterocin L50-like bacteriocins and its correlation with antibiotics. First, to generate spontaneous resistant mutants, L.lactis was exposed to bacteriocin BHT-B. Sequencing of their genomes revealed single nucleotide polymorphisms (SNPs) in the dgkB (yecE) and dxsA genes encoding diacylglycerol kinase and 1-deoxy-D-xylulose 5-phosphate synthase, respectively. Then, selected mutants underwent susceptibility tests with a wide array of bacteriocins and antibiotics. The highest alterations in the sensitivity of studied mutants were seen in the presence of cytoplasmic membrane targeting bacteriocins (K411, Ent7, EntL50, WelM, SalC, nisin) and antibiotics (daptomycin and gramicidin) as well as lipid II cycle-blocking bacteriocins (nisin and Lcn972) and antibiotics (bacitracin). Interestingly, decreased via the SNPs accumulation sensitivity to membrane-active bacteriocins and antibiotics resulted in the concurrently increased vulnerability to bacitracin, carbenicillin, or chlortetracycline. It is suspected that SNPs may result in alterations to the efficiency of the nascent enzymes rather than a total loss of their function as neither deletion nor overexpression of dxsA restored the phenotype observed in spontaneous mutants. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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14 pages, 1435 KiB

Open AccessArticle

The Acquisition of Colistin Resistance Is Associated to the Amplification of a Large Chromosomal Region in Klebsiella pneumoniae kp52145

by María Blanca Sánchez, Alicia Sánchez-Gorostiaga, Trinidad Cuesta and José Luis Martínez

Int. J. Mol. Sci. 2021, 22(2), 649; https://doi.org/10.3390/ijms22020649 - 11 Jan 2021

Cited by 3 | Viewed by 2561

Abstract

The appearance of carbapenem-resistant Klebsiella pneumoniae has increased the use of colistin as a last-resort antibiotic for treating infections by this pathogen. A consequence of its use has been the spread of colistin-resistant strains, in several cases carrying colistin resistance genes. In addition, when susceptible strains are confronted with colistin during treatment, mutation is a major cause of the acquisition of resistance. To analyze the mechanisms of resistance that might be selected during colistin treatment, an experimental evolution assay for 30 days using as a model the clinical K. pneumoniae kp52145 isolate in the presence of increasing amounts of colistin was performed. All evolved populations presented a decreased susceptibility to colistin, without showing cross-resistance to antibiotics belonging to other structural families. We did not find any common mutation in the evolved mutants, neither in already known genes, previously known to be associated with the resistance phenotype, nor in new ones. The only common genetic change observed in the strains that evolved in the presence of colistin was the amplification of a 34 Kb sequence, homologous to a prophage (Enterobacteria phage Fels-2). Our data support that gene amplification can be a driving force in the acquisition of colistin resistance by K. pneumoniae. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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Review

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15 pages, 1805 KiB

Open AccessReview

Gene Transfer Potential of Outer Membrane Vesicles of Gram-Negative Bacteria

by Federica Dell’Annunziata, Veronica Folliero, Rosa Giugliano, Anna De Filippis, Cristina Santarcangelo, Viviana Izzo, Maria Daglia, Massimiliano Galdiero, Carla Renata Arciola and Gianluigi Franci

Int. J. Mol. Sci. 2021, 22(11), 5985; https://doi.org/10.3390/ijms22115985 - 1 Jun 2021

Cited by 52 | Viewed by 5684

Abstract

The increasing spread of multidrug-resistant pathogenic bacteria is one of the major threats to public health worldwide. Bacteria can acquire antibiotic resistance and virulence genes through horizontal gene transfer (HGT). A novel horizontal gene transfer mechanism mediated by outer membrane vesicles (OMVs) has been recently identified. OMVs are rounded nanostructures released during their growth by Gram-negative bacteria. Biologically active toxins and virulence factors are often entrapped within these vesicles that behave as molecular carriers. Recently, OMVs have been reported to contain DNA molecules, but little is known about the vesicle packaging, release, and transfer mechanisms. The present review highlights the role of OMVs in HGT processes in Gram-negative bacteria. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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10 pages, 1155 KiB

Open AccessReview

Colistin Resistance in Aeromonas spp.

by Luis Uriel Gonzalez-Avila, Miguel Angel Loyola-Cruz, Cecilia Hernández-Cortez, Juan Manuel Bello-López and Graciela Castro-Escarpulli

Int. J. Mol. Sci. 2021, 22(11), 5974; https://doi.org/10.3390/ijms22115974 - 1 Jun 2021

Cited by 19 | Viewed by 5461

Abstract

The increase in the use of antimicrobials such as colistin for the treatment of infectious diseases has led to the appearance of Aeromonas strains resistant to this drug. However, resistance to colistin not only occurs in the clinical area but has also been determined in Aeromonas isolates from the environment or animals, which has been determined by the detection of mcr genes that confer a resistance mechanism to colistin. The variants mcr-1, mcr-3, and mcr-5 have been detected in the genus Aeromonas in animal, environmental, and human fluids samples. In this article, an overview of the resistance to colistin in Aeromonas is shown, as well as the generalities of this molecule and the recommended methods to determine colistin resistance to be used in some of the genus Aeromonas. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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20 pages, 976 KiB

Open AccessReview

Ribosome Protection Proteins—“New” Players in the Global Arms Race with Antibiotic-Resistant Pathogens

by Rya Ero, Xin-Fu Yan and Yong-Gui Gao

Int. J. Mol. Sci. 2021, 22(10), 5356; https://doi.org/10.3390/ijms22105356 - 19 May 2021

Cited by 12 | Viewed by 4861

Abstract

Bacteria have evolved an array of mechanisms enabling them to resist the inhibitory effect of antibiotics, a significant proportion of which target the ribosome. Indeed, resistance mechanisms have been identified for nearly every antibiotic that is currently used in clinical practice. With the ever-increasing list of multi-drug-resistant pathogens and very few novel antibiotics in the pharmaceutical pipeline, treatable infections are likely to become life-threatening once again. Most of the prevalent resistance mechanisms are well understood and their clinical significance is recognized. In contrast, ribosome protection protein-mediated resistance has flown under the radar for a long time and has been considered a minor factor in the clinical setting. Not until the recent discovery of the ATP-binding cassette family F protein-mediated resistance in an extensive list of human pathogens has the significance of ribosome protection proteins been truly appreciated. Understanding the underlying resistance mechanism has the potential to guide the development of novel therapeutic approaches to evade or overcome the resistance. In this review, we discuss the latest developments regarding ribosome protection proteins focusing on the current antimicrobial arsenal and pharmaceutical pipeline as well as potential implications for the future of fighting bacterial infections in the time of “superbugs.” Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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13 pages, 4434 KiB

Open AccessReview

pCTX-M3—Structure, Function, and Evolution of a Multi-Resistance Conjugative Plasmid of a Broad Recipient Range

by Izabela Kern-Zdanowicz

Int. J. Mol. Sci. 2021, 22(9), 4606; https://doi.org/10.3390/ijms22094606 - 27 Apr 2021

Cited by 3 | Viewed by 2642

Abstract

pCTX-M3 is the archetypic member of the IncM incompatibility group of conjugative plasmids (recently referred to as IncM2). It is responsible for the worldwide dissemination of numerous antibiotic resistance genes, including those coding for extended-spectrum β-lactamases and conferring resistance to aminoglycosides. The IncM plasmids acquired during evolution diverse mobile genetic elements found in one or two multiple resistance regions, MRR(s), grouping antibiotic resistance genes as well as mobile genetic elements or their remnants. The IncM plasmids can be found in bacteria inhabiting various environments. The information on the structure and biology of pCTX-M3 is integrated in this review. It focuses on the functional modules of pCTX-M3 responsible for its replication, stable maintenance, and conjugative transfer, indicating that the host range of the pCTX-M3 replicon is limited to representatives of the family Enterobacteriaceae (Enterobacterales ord. nov.), while the range of recipients of its conjugation system is wide, comprising Alpha-, Beta-, and Gammaproteobacteria, and also Firmicutes. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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14 pages, 4324 KiB

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Acquisition and Spread of Antimicrobial Resistance: A tet(X) Case Study

by Rustam Aminov

Int. J. Mol. Sci. 2021, 22(8), 3905; https://doi.org/10.3390/ijms22083905 - 9 Apr 2021

Cited by 24 | Viewed by 3997

Abstract

Understanding the mechanisms leading to the rise and dissemination of antimicrobial resistance (AMR) is crucially important for the preservation of power of antimicrobials and controlling infectious diseases. Measures to monitor and detect AMR, however, have been significantly delayed and introduced much later after the beginning of industrial production and consumption of antimicrobials. However, monitoring and detection of AMR is largely focused on bacterial pathogens, thus missing multiple key events which take place before the emergence and spread of AMR among the pathogens. In this regard, careful analysis of AMR development towards recently introduced antimicrobials may serve as a valuable example for the better understanding of mechanisms driving AMR evolution. Here, the example of evolution of tet(X), which confers resistance to the next-generation tetracyclines, is summarised and discussed. Initial mechanisms of resistance to these antimicrobials among pathogens were mostly via chromosomal mutations leading to the overexpression of efflux pumps. High-level resistance was achieved only after the acquisition of flavin-dependent monooxygenase-encoding genes from the environmental microbiota. These genes confer resistance to all tetracyclines, including the next-generation tetracyclines, and thus were termed tet(X). ISCR2 and IS26, as well as a variety of conjugative and mobilizable plasmids of different incompatibility groups, played an essential role in the acquisition of tet(X) genes from natural reservoirs and in further dissemination among bacterial commensals and pathogens. This process, which took place within the last decade, demonstrates how rapidly AMR evolution may progress, taking away some drugs of last resort from our arsenal. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Appearance, Evolution, and Spread)

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