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IJMS
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Drug Resistance: Mechanisms and New Strategies
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Drug Resistance: Mechanisms and New Strategies

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

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 48739

Special Issue Editors

Prof. Dr. Ian Macreadie

E-Mail Website
Guest Editor
School of Science, RMIT University, Bundoora West Campus, PO Box 71, Bundoora, VIC 3083, Australia
Interests: Alzheimer’s disease; yeast models; ageing; stress responses; drug mechanisms; drug resistance; microbial genomics
Special Issues, Collections and Topics in MDPI journals
Dr. John Merlino

E-Mail Website
Guest Editor
Department of Microbiology and Infectious Diseases, The University of Sydney, Sydney, Australia

Special Issue Information

Dear Colleagues,

The ability of microbes to exist in large populations with constantly arising inevitable heterogeneity means that there is capacity for mutants resistant to drugs to reproduce during drug treatments, overcoming individuals undergoing drug treatment. These mutants can further spread throughout the population. In the face of such widespread antimicrobial resistance, new defense solutions are urgently needed.

This Special Issue of IJMS will examine new drugs and new strategies for dealing with microbial threats. We welcome articles on new drugs, new ways of applying drugs and entirely new approaches, including bacteriophage and competing microbe therapies.

Topics include, but are not limited to:

  • Molecular mechanisms of antibiotic resistance and new therapeutic strategies;
  • Drug–microbe interactions;
  • Phage therapeutic strategies;
  • Increasing and modifying host defenses;
  • Host–microbe interactions;
  • Probiotic approaches to drug resistant microbes.

Prof. Dr. Ian Macreadie
Dr. John Merlino
Guest Editors

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.

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Published Papers (7 papers)

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Research

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8 pages, 231 KiB  
Communication
Prevalence of Quinolone Resistance of Extended-Spectrum β-Lactamase-Producing Escherichia coli with ST131-fimH30 in a City Hospital in Hyogo, Japan
by Masazumi Teramae, Kayo Osawa, Katsumi Shigemura, Koichi Kitagawa, Toshiro Shirakawa, Masato Fujisawa and Takayuki Miyara
Int. J. Mol. Sci. 2019, 20(20), 5162; https://doi.org/10.3390/ijms20205162 - 18 Oct 2019
Cited by 6 | Viewed by 2418
Abstract
Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli isolates are known to tolerate superior quinolone antimicrobials compared with other antibacterial agents. Among the clones belonging to sequence type (ST) 131 by multilocus sequence typing, the involvement of the H30-Rx subclone has been reported worldwide with various [...] Read more.
Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli isolates are known to tolerate superior quinolone antimicrobials compared with other antibacterial agents. Among the clones belonging to sequence type (ST) 131 by multilocus sequence typing, the involvement of the H30-Rx subclone has been reported worldwide with various fimH genes encoding type 1 pili. We investigated 83 isolates of ESBL-producing E. coli and performed antimicrobial susceptibility test, CH (fumC/fimH) ST131 by typing the specific PCR. Moreover, mutation analysis of genes involved in quinolone antibiotic resistance (gyrA and parC) and ESBL genotypes were determined. As a result, 54 of 83 isolates (65.1%) of CH40-30 clones corresponding to ST131-fimH30 were detected, and all were resistant to levofloxacin. Mutations associated with this resistance were common, and included S83L and D87N of gyrA and S80I and E84V of parC. Subclone analysis revealed a high proportion of fimH30-non-Rx (40 isolates, 74.1%). Each subclone was characterized by ESBL genotype, and the CTX-M-15 type was mainly seen for fimH30-Rx, with the CTX-M-14 type or CTX-M-27 type seen for fimH30-non-Rx. This study suggests that an increase in ESBL-producing quinolone-resistant E. coli in a city hospital in Hyogo, Japan, was caused by the spread of subclones belonging to fimH30-non-Rx of ST131. Full article
(This article belongs to the Special Issue Drug Resistance: Mechanisms and New Strategies)
18 pages, 1470 KiB  
Article
In Vitro Activity of the Bacteriophage Endolysin HY-133 against Staphylococcus aureus Small-Colony Variants and Their Corresponding Wild Types
by Nina Schleimer, Ursula Kaspar, Dennis Knaack, Christof von Eiff, Sonja Molinaro, Holger Grallert, Evgeny A. Idelevich and Karsten Becker
Int. J. Mol. Sci. 2019, 20(3), 716; https://doi.org/10.3390/ijms20030716 - 7 Feb 2019
Cited by 9 | Viewed by 4881
Abstract
Nasal carriage of methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) represents both a source and a risk factor for subsequent infections. However, existing MRSA decolonization strategies and antibiotic treatment options are hampered by the duration of administration and particularly by the emergence of [...] Read more.
Nasal carriage of methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) represents both a source and a risk factor for subsequent infections. However, existing MRSA decolonization strategies and antibiotic treatment options are hampered by the duration of administration and particularly by the emergence of resistance. Moreover, beyond classical resistance mechanisms, functional resistance as the formation of the small-colony variant (SCV) phenotype may also impair the course and treatment of S. aureus infections. For the recombinant bacteriophage endolysin HY-133, rapid bactericidal and highly selective in vitro activities against MSSA and MRSA has been shown. In order to assess the in vitro efficacy of HY-133 against the SCV phenotype, minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) were evaluated on clinical SCVs, their isogenic wild types, as well as on genetically derived and gentamicin-selected SCVs. For all strains and growth phases, HY-133 MIC and MBC ranged between 0.12 and 1 mg/L. Time-kill studies revealed a fast-acting bactericidal activity of HY-133 resulting in a ≥3 − log10 decrease in CFU/mL within 1 h compared to oxacillin, which required 4–24 h. Since the mode of action of HY-133 was independent of growth phase, resistance pattern, and phenotype, it is a promising candidate for future S. aureus decolonization strategies comprising rapid activity against phenotypic variants exhibiting functional resistance. Full article
(This article belongs to the Special Issue Drug Resistance: Mechanisms and New Strategies)
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12 pages, 2395 KiB  
Article
Ciprofloxacin Enhances the Chemosensitivity of Cancer Cells to ABCB1 Substrates
by Pranav Gupta, Hai-Ling Gao, Yunali V. Ashar, Nishant M. Karadkhelkar, Sabesan Yoganathan and Zhe-Sheng Chen
Int. J. Mol. Sci. 2019, 20(2), 268; https://doi.org/10.3390/ijms20020268 - 11 Jan 2019
Cited by 28 | Viewed by 5004
Abstract
ABCB1 is one of the major drug efflux transporters that is known to cause multidrug resistance (MDR) in cancer patients receiving chemotherapy for the treatment of solid tumors and hematological malignancies. Inhibition of ABCB1 efflux function is important for maintaining the intracellular concentration [...] Read more.
ABCB1 is one of the major drug efflux transporters that is known to cause multidrug resistance (MDR) in cancer patients receiving chemotherapy for the treatment of solid tumors and hematological malignancies. Inhibition of ABCB1 efflux function is important for maintaining the intracellular concentration of chemotherapeutic drugs. Here, we evaluated ciprofloxacin for its ability to reverse MDR caused by the overexpression of ABCB1. Cytotoxicity of ciprofloxacin was determined by the MTT assay. The chemosensitizing effects of ciprofloxacin were determined in combination with ABCB1 substrates. The intracellular accumulation and efflux of ABCB1 substrates was measured by a scintillation counter, and protein expression was determined by the Western blotting. Vanadate-sensitive ATPase assay was performed to determine the effect of ciprofloxacin on the ATPase activity of ABCB1, and docking analysis was done to determine the interaction of ciprofloxacin with ABCB1. Ciprofloxacin significantly potentiated the cytotoxic effects of ABCB1 substrates in ABCB1-overexpressing cells. Furthermore, ciprofloxacin increased the intracellular accumulation and decreased the efflux of [3H]-paclitaxel without altering the expression of ABCB1. Ciprofloxacin stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. Our findings showed that ciprofloxacin potently inhibits the ABCB1 efflux function and it has potential to be developed as a combination anticancer therapy. Full article
(This article belongs to the Special Issue Drug Resistance: Mechanisms and New Strategies)
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Review

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38 pages, 4348 KiB  
Review
Quorum Sensing as Antivirulence Target in Cystic Fibrosis Pathogens
by Viola Camilla Scoffone, Gabriele Trespidi, Laurent R. Chiarelli, Giulia Barbieri and Silvia Buroni
Int. J. Mol. Sci. 2019, 20(8), 1838; https://doi.org/10.3390/ijms20081838 - 13 Apr 2019
Cited by 63 | Viewed by 9497
Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disorder which leads to the secretion of a viscous mucus layer on the respiratory epithelium that facilitates colonization by various bacterial pathogens. The problem of drug resistance has been reported for all the species able [...] Read more.
Cystic fibrosis (CF) is an autosomal recessive genetic disorder which leads to the secretion of a viscous mucus layer on the respiratory epithelium that facilitates colonization by various bacterial pathogens. The problem of drug resistance has been reported for all the species able to colonize the lung of CF patients, so alternative treatments are urgently needed. In this context, a valid approach is to investigate new natural and synthetic molecules for their ability to counteract alternative pathways, such as virulence regulating quorum sensing (QS). In this review we describe the pathogens most commonly associated with CF lung infections: Staphylococcus aureus, Pseudomonas aeruginosa, species of the Burkholderia cepacia complex and the emerging pathogens Stenotrophomonas maltophilia, Haemophilus influenzae and non-tuberculous Mycobacteria. For each bacterium, the QS system(s) and the molecules targeting the different components of this pathway are described. The amount of investigations published in the last five years clearly indicate the interest and the expectations on antivirulence therapy as an alternative to classical antibiotics. Full article
(This article belongs to the Special Issue Drug Resistance: Mechanisms and New Strategies)
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13 pages, 952 KiB  
Review
Fighting AMR in the Healthcare Environment: Microbiome-Based Sanitation Approaches and Monitoring Tools
by Maria D’Accolti, Irene Soffritti, Sante Mazzacane and Elisabetta Caselli
Int. J. Mol. Sci. 2019, 20(7), 1535; https://doi.org/10.3390/ijms20071535 - 27 Mar 2019
Cited by 41 | Viewed by 7643
Abstract
Healthcare-associated infections (HAIs) affect up to 15% of all hospitalized patients, representing a global concern. Major causes include the persistent microbial contamination of hospital environment, and the growing antimicrobial-resistance (AMR) of HAI-associated microbes. The hospital environment represents in fact a reservoir of potential [...] Read more.
Healthcare-associated infections (HAIs) affect up to 15% of all hospitalized patients, representing a global concern. Major causes include the persistent microbial contamination of hospital environment, and the growing antimicrobial-resistance (AMR) of HAI-associated microbes. The hospital environment represents in fact a reservoir of potential pathogens, continuously spread by healthcare personnel, visiting persons and hospitalized patients. The control of contamination has been so far addressed by the use of chemical-based sanitation procedures, which however have limitations, as testified by the persistence of contamination itself and by the growing AMR of hospital microbes. Here we review the results collected by a microbial-based sanitation system, inspired by the microbiome balance principles, in obtaining more effective control of microbial contamination and AMR. Whatever the sanitation system used, an important aspect of controlling AMR and HAIs relates to the ability to check any variation of a microbial population rapidly and effectively, thus effective monitoring procedures are also described. Full article
(This article belongs to the Special Issue Drug Resistance: Mechanisms and New Strategies)
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15 pages, 260 KiB  
Review
An Overview on Streptococcus bovis/Streptococcus equinus Complex Isolates: Identification to the Species/Subspecies Level and Antibiotic Resistance
by Arianna Pompilio, Giovanni Di Bonaventura and Giovanni Gherardi
Int. J. Mol. Sci. 2019, 20(3), 480; https://doi.org/10.3390/ijms20030480 - 23 Jan 2019
Cited by 39 | Viewed by 7676
Abstract
Streptococcus bovis/Streptococcus equinus complex (SBSEC), a non-enterococcal group D Streptococcus spp. complex, has been described as commensal bacteria in humans and animals, with a fecal carriage rate in humans varying from 5% to over 60%. Among streptococci, SBSEC isolates represent the [...] Read more.
Streptococcus bovis/Streptococcus equinus complex (SBSEC), a non-enterococcal group D Streptococcus spp. complex, has been described as commensal bacteria in humans and animals, with a fecal carriage rate in humans varying from 5% to over 60%. Among streptococci, SBSEC isolates represent the most antibiotic-resistant species—with variable resistance rates reported for clindamycin, erythromycin, tetracycline, and levofloxacin—and might act as a reservoir of multiple acquired genes. Moreover, reduced susceptibility to penicillin and vancomycin associated with mobile genetic elements have also been detected, although rarely. Since the association of SBSEC bacteremia and colon lesions, infective endocarditis and hepatobiliary diseases has been established, particularly in elderly individuals, an accurate identification of SBSEC isolates to the species and subspecies level, as well as the evaluation of antibiotic resistance, are needed. In this paper, we reviewed the major methods used to identify SBSEC isolates and the antimicrobial resistance rates reported in the scientific literature among SBSEC species. Full article
(This article belongs to the Special Issue Drug Resistance: Mechanisms and New Strategies)
23 pages, 300 KiB  
Review
Contribution of HIV Infection, AIDS, and Antiretroviral Therapy to Exocrine Pathogenesis in Salivary and Lacrimal Glands
by Imran Nizamuddin, Peter Koulen and Carole P. McArthur
Int. J. Mol. Sci. 2018, 19(9), 2747; https://doi.org/10.3390/ijms19092747 - 13 Sep 2018
Cited by 17 | Viewed by 10791
Abstract
The structure and function of exocrine glands are negatively affected by human immunodeficiency virus (HIV) infection and its co-morbidities, including innate and adaptive immune responses. At the same time, exocrine function may also be influenced by pharmacotherapies directed at the infectious agents. Here, [...] Read more.
The structure and function of exocrine glands are negatively affected by human immunodeficiency virus (HIV) infection and its co-morbidities, including innate and adaptive immune responses. At the same time, exocrine function may also be influenced by pharmacotherapies directed at the infectious agents. Here, we briefly review the role of the salivary glands and lacrimal glands in normal physiology and exocrine pathogenesis within the context of HIV infection and acquired immune deficiency syndrome (AIDS), including the contribution of antiretroviral therapies on both. Subsequently, we discuss the impact of HIV infection and the types of antiretroviral therapy on disease management and therapy development efforts. Full article
(This article belongs to the Special Issue Drug Resistance: Mechanisms and New Strategies)
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