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Antibiotics
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Mechanisms of Antibiotic Resistance
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Mechanisms of Antibiotic Resistance

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 March 2014) | Viewed by 113695

Special Issue Editor

Dr. Sergei Vakulenko

E-Mail Website
Guest Editor
Department Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
Interests: mechanisms of resistance to beta-lactam and aminoglycoside antibiotics; beta-lactamases; aminoglycoside-modifying enzymes; enzyme kinetics; structure-activity relationships

Special Issue Information

Dear Colleagues,

Since their introduction into clinical practice seven decades ago, antibiotics have helped to save hundreds of millions of lives. The overwhelming success of the first antibiotics was due to the fact that the majority of clinically important bacterial pathogens were highly susceptible to these compounds. Subsequent widespread, and often uncontrolled, use of antimicrobial agents resulted in the selection and dissemination of antibiotic-resistant bacteria. Presently, the number of bacterial isolates resistant to the majority or even all available antibiotics steadily increases. With respect to such resistant pathogens, we already have reached the so-called post-antibiotic era, where, despite the availability of hundreds of antibiotics, there is no available treatment and the mortality rates from infections could reach as high as those observed in the pre-antibiotic era.

"Antibiotics" will publish a Special Issue dedicated to antibiotic resistance in bacteria. It is my pleasure to invite submissions of review and research papers focused on studies of various aspects of microbial drug resistance, with a major emphasis on the genetic, molecular and structural mechanisms of antibiotic resistance and the evolution of antibiotic-resistance determinants.

Dr. Sergei Vakulenko
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

  • antibiotic resistance genes and mechanisms of their dissemination in bacterial populations
  • epidemiology of antibiotic resistance
  • kinetic and structural studies of antibiotic resistance enzymes
  • non-enzymatic mechanisms of antibiotic resistance

Published Papers (7 papers)

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Research

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3473 KiB  
Article
Genomic, Transcriptomic and Metabolomic Studies of Two Well-Characterized, Laboratory-Derived Vancomycin-Intermediate Staphylococcus aureus Strains Derived from the Same Parent Strain
by Dipti S. Hattangady, Atul K. Singh, Arun Muthaiyan, Radheshyam K. Jayaswal, John E. Gustafson, Alexander V. Ulanov, Zhong Li, Brian J. Wilkinson and Richard F. Pfeltz
Antibiotics 2015, 4(1), 76-112; https://doi.org/10.3390/antibiotics4010076 - 04 Feb 2015
Cited by 13 | Viewed by 8517
Abstract
Complete genome comparisons, transcriptomic and metabolomic studies were performed on two laboratory-selected, well-characterized vancomycin-intermediate Staphylococcus aureus (VISA) derived from the same parent MRSA that have changes in cell wall composition and decreased autolysis. A variety of mutations were found in the VISA, with [...] Read more.
Complete genome comparisons, transcriptomic and metabolomic studies were performed on two laboratory-selected, well-characterized vancomycin-intermediate Staphylococcus aureus (VISA) derived from the same parent MRSA that have changes in cell wall composition and decreased autolysis. A variety of mutations were found in the VISA, with more in strain 13136p−m+V20 (vancomycin MIC = 16 µg/mL) than strain 13136p−m+V5 (MIC = 8 µg/mL). Most of the mutations have not previously been associated with the VISA phenotype; some were associated with cell wall metabolism and many with stress responses, notably relating to DNA damage. The genomes and transcriptomes of the two VISA support the importance of gene expression regulation to the VISA phenotype. Similarities in overall transcriptomic and metabolomic data indicated that the VISA physiologic state includes elements of the stringent response, such as downregulation of protein and nucleotide synthesis, the pentose phosphate pathway and nutrient transport systems. Gene expression for secreted virulence determinants was generally downregulated, but was more variable for surface-associated virulence determinants, although capsule formation was clearly inhibited. The importance of activated stress response elements could be seen across all three analyses, as in the accumulation of osmoprotectant metabolites such as proline and glutamate. Concentrations of potential cell wall precursor amino acids and glucosamine were increased in the VISA strains. Polyamines were decreased in the VISA, which may facilitate the accrual of mutations. Overall, the studies confirm the wide variability in mutations and gene expression patterns that can lead to the VISA phenotype. Full article
(This article belongs to the Special Issue Mechanisms of Antibiotic Resistance)
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Review

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820 KiB  
Review
Old and New Glycopeptide Antibiotics: Action and Resistance
by Elisa Binda, Flavia Marinelli and Giorgia Letizia Marcone
Antibiotics 2014, 3(4), 572-594; https://doi.org/10.3390/antibiotics3040572 - 04 Nov 2014
Cited by 110 | Viewed by 24155
Abstract
Glycopeptides are considered antibiotics of last resort for the treatment of life-threatening infections caused by relevant Gram-positive human pathogens, such as Staphylococcus aureus, Enterococcus spp. and Clostridium difficile. The emergence of glycopeptide-resistant clinical isolates, first among enterococci and then in staphylococci, [...] Read more.
Glycopeptides are considered antibiotics of last resort for the treatment of life-threatening infections caused by relevant Gram-positive human pathogens, such as Staphylococcus aureus, Enterococcus spp. and Clostridium difficile. The emergence of glycopeptide-resistant clinical isolates, first among enterococci and then in staphylococci, has prompted research for second generation glycopeptides and a flurry of activity aimed at understanding resistance mechanisms and their evolution. Glycopeptides are glycosylated non-ribosomal peptides produced by a diverse group of soil actinomycetes. They target Gram-positive bacteria by binding to the acyl-D-alanyl-D-alanine (D-Ala-D-Ala) terminus of the growing peptidoglycan on the outer surface of the cytoplasmatic membrane. Glycopeptide-resistant organisms avoid such a fate by replacing the D-Ala-D-Ala terminus with D-alanyl-D-lactate (D-Ala-D-Lac) or D-alanyl-D-serine (D-Ala-D-Ser), thus markedly reducing antibiotic affinity for the cellular target. Resistance has manifested itself in enterococci and staphylococci largely through the expression of genes (named van) encoding proteins that reprogram cell wall biosynthesis and, thus, evade the action of the antibiotic. These resistance mechanisms were most likely co-opted from the glycopeptide producing actinomycetes, which use them to avoid suicide during antibiotic production, rather than being orchestrated by pathogen bacteria upon continued treatment. van-like gene clusters, similar to those described in enterococci, were in fact identified in many glycopeptide-producing actinomycetes, such as Actinoplanes teichomyceticus, which produces teicoplanin, and Streptomyces toyocaensis, which produces the A47934 glycopeptide. In this paper, we describe the natural and semi-synthetic glycopeptide antibiotics currently used as last resort drugs for Gram-positive infections and compare the van gene-based strategies of glycopeptide resistance among the pathogens and the producing actinomycetes. Particular attention is given to the strategy of immunity recently described in Nonomuraea sp. ATCC 39727. Nonomuraea sp. ATCC 39727 is the producer of A40926, which is the natural precursor of the second generation semi-synthetic glycopeptide dalbavancin, very recently approved for acute bacterial skin and skin structure infections. A thorough understanding of glycopeptide immunity in this producing microorganism may be particularly relevant to predict and eventually control the evolution of resistance that might arise following introduction of dalbavancin and other second generation glycopeptides into clinics. Full article
(This article belongs to the Special Issue Mechanisms of Antibiotic Resistance)
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1233 KiB  
Review
Acquired Class D β-Lactamases
by Nuno T. Antunes and Jed F. Fisher
Antibiotics 2014, 3(3), 398-434; https://doi.org/10.3390/antibiotics3030398 - 21 Aug 2014
Cited by 66 | Viewed by 9187
Abstract
The Class D β-lactamases have emerged as a prominent resistance mechanism against β-lactam antibiotics that previously had efficacy against infections caused by pathogenic bacteria, especially by Acinetobacter baumannii and the Enterobacteriaceae. The phenotypic and structural characteristics of these enzymes correlate to activities [...] Read more.
The Class D β-lactamases have emerged as a prominent resistance mechanism against β-lactam antibiotics that previously had efficacy against infections caused by pathogenic bacteria, especially by Acinetobacter baumannii and the Enterobacteriaceae. The phenotypic and structural characteristics of these enzymes correlate to activities that are classified either as a narrow spectrum, an extended spectrum, or a carbapenemase spectrum. We focus on Class D β-lactamases that are carried on plasmids and, thus, present particular clinical concern. Following a historical perspective, the susceptibility and kinetics patterns of the important plasmid-encoded Class D β-lactamases and the mechanisms for mobilization of the chromosomal Class D β-lactamases are discussed. Full article
(This article belongs to the Special Issue Mechanisms of Antibiotic Resistance)
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558 KiB  
Review
Drug Resistance Mechanisms in Mycobacterium tuberculosis
by Juan Carlos Palomino and Anandi Martin
Antibiotics 2014, 3(3), 317-340; https://doi.org/10.3390/antibiotics3030317 - 02 Jul 2014
Cited by 251 | Viewed by 25856
Abstract
Tuberculosis (TB) is a serious public health problem worldwide. Its situation is worsened by the presence of multidrug resistant (MDR) strains of Mycobacterium tuberculosis, the causative agent of the disease. In recent years, even more serious forms of drug resistance have been [...] Read more.
Tuberculosis (TB) is a serious public health problem worldwide. Its situation is worsened by the presence of multidrug resistant (MDR) strains of Mycobacterium tuberculosis, the causative agent of the disease. In recent years, even more serious forms of drug resistance have been reported. A better knowledge of the mechanisms of drug resistance of M. tuberculosis and the relevant molecular mechanisms involved will improve the available techniques for rapid drug resistance detection and will help to explore new targets for drug activity and development. This review article discusses the mechanisms of action of anti-tuberculosis drugs and the molecular basis of drug resistance in M. tuberculosis. Full article
(This article belongs to the Special Issue Mechanisms of Antibiotic Resistance)
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2966 KiB  
Review
Evolution of Metallo-β-lactamases: Trends Revealed by Natural Diversity and in vitro Evolution
by María-Rocío Meini, Leticia I. Llarrull and Alejandro J. Vila
Antibiotics 2014, 3(3), 285-316; https://doi.org/10.3390/antibiotics3030285 - 01 Jul 2014
Cited by 63 | Viewed by 11844
Abstract
The production of β-lactamase enzymes is one of the most distributed resistance mechanisms towards β-lactam antibiotics. Metallo-β-lactamases constitute a worrisome group of these kinds of enzymes, since they present a broad spectrum profile, being able to hydrolyze not only penicillins, but also the [...] Read more.
The production of β-lactamase enzymes is one of the most distributed resistance mechanisms towards β-lactam antibiotics. Metallo-β-lactamases constitute a worrisome group of these kinds of enzymes, since they present a broad spectrum profile, being able to hydrolyze not only penicillins, but also the latest generation of cephalosporins and carbapenems, which constitute at present the last resource antibiotics. The VIM, IMP, and NDM enzymes comprise the main groups of clinically relevant metallo-β-lactamases. Here we present an update of the features of the natural variants that have emerged and of the ones that have been engineered in the laboratory, in an effort to find sequence and structural determinants of substrate preferences. This knowledge is of upmost importance in novel drug design efforts. We also discuss the advances in knowledge achieved by means of in vitro directed evolution experiments, and the potential of this approach to predict natural evolution of metallo-β-lactamases.The production of β-lactamase enzymes is one of the most distributed resistance mechanisms towards β-lactam antibiotics. Metallo-β-lactamases constitute a worrisome group of these kinds of enzymes, since they present a broad spectrum profile, being able to hydrolyze not only penicillins, but also the latest generation of cephalosporins and carbapenems, which constitute at present the last resource antibiotics. The VIM, IMP, and NDM enzymes comprise the main groups of clinically relevant metallo-β-lactamases. Here we present an update of the features of the natural variants that have emerged and of the ones that have been engineered in the laboratory, in an effort to find sequence and structural determinants of substrate preferences. This knowledge is of upmost importance in novel drug design efforts. We also discuss the advances in knowledge achieved by means of in vitro directed evolution experiments, and the potential of this approach to predict natural evolution of metallo-β-lactamases. Full article
(This article belongs to the Special Issue Mechanisms of Antibiotic Resistance)
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1041 KiB  
Review
β-Lactam Antibiotics Renaissance
by Wenling Qin, Mauro Panunzio and Stefano Biondi
Antibiotics 2014, 3(2), 193-215; https://doi.org/10.3390/antibiotics3020193 - 09 May 2014
Cited by 41 | Viewed by 11732
Abstract
Since the 1940s β-lactam antibiotics have been used to treat bacterial infections. However, emergence and dissemination of β-lactam resistance has reached the point where many marketed β-lactams no longer are clinically effective. The increasing prevalence of multidrug-resistant bacteria and the progressive withdrawal of [...] Read more.
Since the 1940s β-lactam antibiotics have been used to treat bacterial infections. However, emergence and dissemination of β-lactam resistance has reached the point where many marketed β-lactams no longer are clinically effective. The increasing prevalence of multidrug-resistant bacteria and the progressive withdrawal of pharmaceutical companies from antibiotic research have evoked a strong reaction from health authorities, who have implemented initiatives to encourage the discovery of new antibacterials. Despite this gloomy scenario, several novel β-lactam antibiotics and β-lactamase inhibitors have recently progressed into clinical trials, and many more such compounds are being investigated. Here we seek to provide highlights of recent developments relating to the discovery of novel β-lactam antibiotics and β-lactamase inhibitors. Full article
(This article belongs to the Special Issue Mechanisms of Antibiotic Resistance)
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919 KiB  
Review
Molecular Targets of β-Lactam-Based Antimicrobials: Beyond the Usual Suspects
by Monika I. Konaklieva
Antibiotics 2014, 3(2), 128-142; https://doi.org/10.3390/antibiotics3020128 - 03 Apr 2014
Cited by 39 | Viewed by 21080
Abstract
The common practice in antibacterial drug development has been to rapidly make an attempt to find ever-more stable and broad-spectrum variants for a particular antibiotic, once a drug resistance for that antibiotic is detected. We are now facing bacterial resistance toward our clinically [...] Read more.
The common practice in antibacterial drug development has been to rapidly make an attempt to find ever-more stable and broad-spectrum variants for a particular antibiotic, once a drug resistance for that antibiotic is detected. We are now facing bacterial resistance toward our clinically relevant antibiotics of such a magnitude that the conversation for antimicrobial drug development ought to include effective new antibiotics with alternative mechanisms of action. The electrophilic β-lactam ring is amenable for the inhibition of different enzyme classes by a suitable decoration of the core scaffold. Monocyclic β-lactams lacking an ionizable group at the lactam nitrogen exhibit target preferences toward bacterial enzymes important for resistance and virulence. The present review intends to draw attention to the versatility of the β-lactams as antimicrobials with “unusual” molecular targets. Full article
(This article belongs to the Special Issue Mechanisms of Antibiotic Resistance)
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