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Antibiotics
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Genetic Background of Antimicrobial Resistance
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Genetic Background of Antimicrobial Resistance

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Mechanism and Evolution of Antibiotic Resistance".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 27419

Special Issue Editor

Dr. Norbert Solymosi

E-Mail Website
Guest Editor
Centre for Bioinformatics, University of Veterinary Medicine Budapest, Budapest, Hungary
Interests: genetic background of antimicrobial resistance; genomics; epidemiology

Special Issue Information

Dear Colleagues,

The increasing prevalence of antimicrobial resistance (AMR) is a significant threat to global health. The widespread use of antibiotics in human healthcare and animal disease control is increasingly shortening the time it takes for resistant strains to develop. The background of the phenotypic appearance of AMR is determined by genetic factors such as antimicrobial genes (ARGs) and single-nucleotide polymorphisms, among others. While ARGs often occur with significant sequential variability, the effect of this diversity on AMR is less explored. Moreover, little is known about the structural properties of the genome that determine ARG expression. Due to these genomic features, the antimicrobial resistance potential is not necessarily activated phenotypically. A crucial point in the research on AMR spread is the identification of genetic factors that facilitate the horizontal gene transfer of ARGs between bacteria. Within the range of possible MGEs, the significance of plasmid and phage environments is beyond question. On the other hand, the functional evaluation of chromosomal mobile genetic elements supporting the ARG transferability requires further scientific deliberation.

This Special Issue solicits manuscript submissions to improve our understanding of the genetic background of AMR. Submissions on the organization of genes and the genetic environment of ARGs that influence the AMR phenotypes are particularly encouraged.

Dr. Norbert Solymosi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antimicrobial resistance genes
  • resistance determinants
  • gene polymorphism
  • horizontal gene transfer
  • plasmids
  • phages
  • mobile genetic elements
  • genome organization
  • gene expression

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Published Papers (7 papers)

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Research

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13 pages, 2201 KiB  
Article
Spread of blaCTX-M-9 and Other Clinically Relevant Resistance Genes, Such as mcr-9 and qnrA1, Driven by IncHI2-ST1 Plasmids in Clinical Isolates of Monophasic Salmonella enterica Serovar Typhimurium ST34
by Xenia Vázquez, Javier Fernández, Miriam Alkorta, María de Toro, M. Rosario Rodicio and Rosaura Rodicio
Antibiotics 2023, 12(3), 547; https://doi.org/10.3390/antibiotics12030547 - 9 Mar 2023
Cited by 4 | Viewed by 2140
Abstract
The monophasic 4,[5],12:i:-variant of Salmonella enterica serovar Typhimurium with sequence type ST34 has become one of the most prevalent non-typhoidal salmonellae worldwide. In the present study, we thoroughly characterized seven isolates of this variant detected in a Spanish hospital and selected based on [...] Read more.
The monophasic 4,[5],12:i:-variant of Salmonella enterica serovar Typhimurium with sequence type ST34 has become one of the most prevalent non-typhoidal salmonellae worldwide. In the present study, we thoroughly characterized seven isolates of this variant detected in a Spanish hospital and selected based on cefotaxime resistance and cefoxitin susceptibility, mediated by blaCTX-M-9. For this, conventional microbiological techniques, together with whole genome sequencing performed with the Illumina platform, were applied. All selected isolates carried the resistance region RR or variants therein, and most also contained the SGI-4 genomic island. These chromosomal elements, typically associated with monophasic S. Typhimurium ST34, confer resistance to traditional antibiotics (ampicillin, streptomycin, sulfonamides, and tetracycline) and tolerance to heavy metals (mercury, silver, and copper). In addition, each isolate carried a large IncHI2-ST1 conjugative plasmid containing additional or redundant resistance genes. All harbored the blaCTX-M-9 gene responsible for cefotaxime resistance, whereas the qnrA1 gene mediating fluoroquinolone resistance was detected in two of the plasmids. These genes were embedded in ISCR1-bearing complex class 1 integrons, specifically In60-like and In36-like. The mcr-9 gene was present in all but one of the IncHI2-ST1 plasmids found in the analyzed isolates, which were nevertheless susceptible to colistin. Most of the resistance genes of plasmid origin clustered within a highly complex and variable region. The observed diversity results in a wide range of resistance phenotypes, enabling bacterial adaptation to selective pressure posed by the use of antimicrobials. Full article
(This article belongs to the Special Issue Genetic Background of Antimicrobial Resistance)
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15 pages, 2290 KiB  
Article
Regulatory Landscape of the Pseudomonas aeruginosa Phosphoethanolamine Transferase Gene eptA in the Context of Colistin Resistance
by Matteo Cervoni, Davide Sposato, Alessandra Lo Sciuto and Francesco Imperi
Antibiotics 2023, 12(2), 200; https://doi.org/10.3390/antibiotics12020200 - 18 Jan 2023
Cited by 7 | Viewed by 2629
Abstract
Pseudomonas aeruginosa has the genetic potential to acquire colistin resistance through the modification of lipopolysaccharide by the addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) or phosphoethanolamine (PEtN), mediated by the arn operon or the eptA gene, respectively. However, in vitro evolution experiments and genetic analysis of [...] Read more.
Pseudomonas aeruginosa has the genetic potential to acquire colistin resistance through the modification of lipopolysaccharide by the addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) or phosphoethanolamine (PEtN), mediated by the arn operon or the eptA gene, respectively. However, in vitro evolution experiments and genetic analysis of clinical isolates indicate that lipopolysaccharide modification with L-Ara4N is invariably preferred over PEtN addition as the colistin resistance mechanism in this bacterium. Since little is known about eptA regulation in P. aeruginosa, we generated luminescent derivatives of the reference strain P. aeruginosa PAO1 to monitor arn and eptA promoter activity. We performed transposon mutagenesis assays to compare the likelihood of acquiring mutations leading to arn or eptA induction and to identify eptA regulators. The analysis revealed that eptA was slightly induced under certain stress conditions, such as arginine or biotin depletion and accumulation of the signal molecule diadenosine tetraphosphate, but the induction did not confer colistin resistance. Moreover, we demonstrated that spontaneous mutations leading to colistin resistance invariably triggered arn rather than eptA expression, and that eptA was not induced in resistant mutants upon colistin exposure. Overall, these results suggest that the contribution of eptA to colistin resistance in P. aeruginosa may be limited by regulatory restraints. Full article
(This article belongs to the Special Issue Genetic Background of Antimicrobial Resistance)
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12 pages, 1046 KiB  
Article
Gene–Gene Interactions Reduce Aminoglycoside Susceptibility of Pseudomonas aeruginosa through Efflux Pump-Dependent and -Independent Mechanisms
by Aswin Thacharodi and Iain L. Lamont
Antibiotics 2023, 12(1), 152; https://doi.org/10.3390/antibiotics12010152 - 11 Jan 2023
Cited by 6 | Viewed by 2087
Abstract
Pseudomonas aeruginosa causes a wide range of acute and chronic infections. Aminoglycosides are a cornerstone of treatment, but isolates are often resistant. The purpose of this research was to better understand the genetic basis of aminoglycoside resistance in P. aeruginosa. Bioinformatic approaches [...] Read more.
Pseudomonas aeruginosa causes a wide range of acute and chronic infections. Aminoglycosides are a cornerstone of treatment, but isolates are often resistant. The purpose of this research was to better understand the genetic basis of aminoglycoside resistance in P. aeruginosa. Bioinformatic approaches identified mutations in resistance-associated genes in the clinical isolates of P. aeruginosa. The common mutations were then engineered into the genome of P. aeruginosa reference strain PAO1. Mutations in the elongation factor gene fusA1 caused the biggest reduction in aminoglycoside susceptibility, with mutations in the two-component regulator gene amgS and the efflux pump regulator gene mexZ having less impact. This susceptibility was further reduced by combinations of mutations. Mutations in fusA1, amgS and mexZ all increased the expression of the mexXY efflux pump that is strongly associated with aminoglycoside resistance. Furthermore, the fusA1 amgS mexZ triple mutant had the highest efflux pump gene expression. Engineering fusA1 and amgS mutants lacking this efflux pump showed that fusA1 and amgS also reduce aminoglycoside susceptibility through additional mechanisms. The fusA1 and amgS mutations reduced bacterial growth, showing that these mutations have a fitness cost. Our findings demonstrate the complex interplay between mutations, efflux pump expression and other mechanisms for reducing the susceptibility of P. aeruginosa to aminoglycosides. Full article
(This article belongs to the Special Issue Genetic Background of Antimicrobial Resistance)
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12 pages, 2498 KiB  
Article
Transcriptomic and Metabolomic Analysis of a Fusidic Acid-Selected fusA Mutant of Staphylococcus aureus
by Sushim K. Gupta, Richard F. Pfeltz, Brian J. Wilkinson and John E. Gustafson
Antibiotics 2022, 11(8), 1051; https://doi.org/10.3390/antibiotics11081051 - 3 Aug 2022
Cited by 5 | Viewed by 2323
Abstract
Physiological experimentation, transcriptomics, and metabolomics were engaged to compare a fusidic acid-resistant Staphylococcus aureus mutant SH10001st-2 to its parent strain SH1000. SH10001st-2 harbored a mutation (H457Y) in the gene fusA which encodes the fusidic acid target, elongation factor G, as well as mutations [...] Read more.
Physiological experimentation, transcriptomics, and metabolomics were engaged to compare a fusidic acid-resistant Staphylococcus aureus mutant SH10001st-2 to its parent strain SH1000. SH10001st-2 harbored a mutation (H457Y) in the gene fusA which encodes the fusidic acid target, elongation factor G, as well as mutations in a putative phage gene of unknown function. SH10001st-2 grew slower than SH1000 at three temperatures and had reduced coagulase activity, two indicators of the fitness penalty reported for fusA-mediated fusidic acid- resistance in the absence of compensatory mutations. Despite the difference in growth rates, the levels of O2 consumption and CO2 production were comparable. Transcriptomic profiling revealed 326 genes were upregulated and 287 were downregulated in SH10001st-2 compared to SH1000. Cell envelope and transport and binding protein genes were the predominant functional categories of both upregulated and downregulated genes in SH10001st-2. Genes of virulence regulators, notably the agr and kdp systems, were highly upregulated as were genes encoding capsule production. Contrary to what is expected of mid-exponential phase cells, genes encoding secreted virulence factors were generally upregulated while those for adhesion-associated virulence factors were downregulated in SH10001st-2. Metabolomic analysis showed an overall increase in metabolite pools in SH10001st-2 compared to SH1000, mostly for amino acids and sugars. Slowed growth and metabolite accumulation may be byproducts of fusA mutation-mediated protein synthesis impairment, but the overall results indicate that SH10001st-2 is compensating for the H457Y fitness penalty by repurposing its virulence machinery, in conjunction with increasing metabolite uptake capacity, in order to increase nutrient acquisition. Full article
(This article belongs to the Special Issue Genetic Background of Antimicrobial Resistance)
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9 pages, 715 KiB  
Article
Occurrence of Antibiotic Resistance in the Mediterranean Sea
by Delia Gambino, Dario Savoca, Arianna Sucato, Valeria Gargano, Antonino Gentile, Licia Pantano, Domenico Vicari and Rosa Alduina
Antibiotics 2022, 11(3), 332; https://doi.org/10.3390/antibiotics11030332 - 3 Mar 2022
Cited by 12 | Viewed by 3887
Abstract
Seawater could be considered a reservoir of antibiotic-resistant bacteria and antibiotic resistance genes. In this communication, we evaluated the presence of bacterial strains in seawater collected from different coasts of Sicily by combining microbiological and molecular methods. Specifically, we isolated viable bacteria that [...] Read more.
Seawater could be considered a reservoir of antibiotic-resistant bacteria and antibiotic resistance genes. In this communication, we evaluated the presence of bacterial strains in seawater collected from different coasts of Sicily by combining microbiological and molecular methods. Specifically, we isolated viable bacteria that were tested for their antibiotic resistance profile and detected both antibiotic and heavy metal resistance genes. Both antibiotic-resistant Gram-negative bacteria, Vibrio and Aeromonas, and specific antibiotic resistance genes were found in the seawater samples. Alarming levels of resistance were determined towards cefazolin, streptomycin, amoxicillin/clavulanic acid, ceftriaxone, and sulfamethoxazole/trimethoprim, and mainly genes conferring resistance to β-lactamic and sulfonamide antibiotics were detected. This survey, on the one hand, presents a picture of the actual situation, showing the pollution status of the Tyrrhenian coast of Sicily, and, on the other hand, can be considered as a baseline to be used as a reference time for future analysis. Full article
(This article belongs to the Special Issue Genetic Background of Antimicrobial Resistance)
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Review

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12 pages, 515 KiB  
Review
Review and Comparison of Antimicrobial Resistance Gene Databases
by Márton Papp and Norbert Solymosi
Antibiotics 2022, 11(3), 339; https://doi.org/10.3390/antibiotics11030339 - 4 Mar 2022
Cited by 35 | Viewed by 10784 | Correction
Abstract
As the prevalence of antimicrobial resistance genes is increasing in microbes, we are facing the return of the pre-antibiotic era. Consecutively, the number of studies concerning antibiotic resistance and its spread in the environment is rapidly growing. Next generation sequencing technologies are widespread [...] Read more.
As the prevalence of antimicrobial resistance genes is increasing in microbes, we are facing the return of the pre-antibiotic era. Consecutively, the number of studies concerning antibiotic resistance and its spread in the environment is rapidly growing. Next generation sequencing technologies are widespread used in many areas of biological research and antibiotic resistance is no exception. For the rapid annotation of whole genome sequencing and metagenomic results considering antibiotic resistance, several tools and data resources were developed. These databases, however, can differ fundamentally in the number and type of genes and resistance determinants they comprise. Furthermore, the annotation structure and metadata stored in these resources can also contribute to their differences. Several previous reviews were published on the tools and databases of resistance gene annotation; however, to our knowledge, no previous review focused solely and in depth on the differences in the databases. In this review, we compare the most well-known and widely used antibiotic resistance gene databases based on their structure and content. We believe that this knowledge is fundamental for selecting the most appropriate database for a research question and for the development of new tools and resources of resistance gene annotation. Full article
(This article belongs to the Special Issue Genetic Background of Antimicrobial Resistance)
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Other

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8 pages, 1178 KiB  
Brief Report
Effect of Subinhibitory Concentrations of Antibiotics and Disinfectants on ISAba-Mediated Inactivation of Lipooligosaccharide Biosynthesis Genes in Acinetobacter baumannii
by Héctor Olmeda-López, Andrés Corral-Lugo and Michael J. McConnell
Antibiotics 2021, 10(10), 1259; https://doi.org/10.3390/antibiotics10101259 - 16 Oct 2021
Cited by 4 | Viewed by 2272
Abstract
Inactivation of the lipooligosaccharide (LOS) biosynthesis genes lpxA, lpxC and lpxD by ISAba insertion elements results in high-level resistance to colistin in A. baumannii. In the present study, we quantify the rate of spontaneous insertional inactivation of LOS biosynthesis genes [...] Read more.
Inactivation of the lipooligosaccharide (LOS) biosynthesis genes lpxA, lpxC and lpxD by ISAba insertion elements results in high-level resistance to colistin in A. baumannii. In the present study, we quantify the rate of spontaneous insertional inactivation of LOS biosynthesis genes by ISAba elements in the ATCC 19606-type strain and two multidrug clinical isolates. Using insertional inactivation of lpxC by ISAba11 in the ATCC 19606 strain as a model, we determine the effect of several subinhibitory concentrations of the antibiotics, namely tetracycline, ciprofloxacin, meropenem, kanamycin and rifampicin, as well as the disinfectants ethanol and chlorhexidine on ISAba11 insertion frequencies. Notably, subinhibitory concentrations of tetracycline significantly increased ISAba11 insertion, and rifampicin completely inhibited the emergence of colistin resistance due to ISAba11 inactivation of lpxC. Sequencing of ISAba11 insertion sites within the lpxC gene demonstrated that insertions clustered between nucleotides 382 and 618 (58.3% of unique insertions detected), indicating that this may be a hotspot for ISAba11 insertion. The alignment of insertion sites revealed a semi-conserved AT-rich consensus sequence upstream of the ISAba11 insertion site, suggesting that ISAba11 insertion sites may be sequence-dependent. This study explores previously uncharacterized aspects regarding the acquisition of colistin resistance through insertional activation in LOS biosynthesis genes in A. baumannii. Full article
(This article belongs to the Special Issue Genetic Background of Antimicrobial Resistance)
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