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Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation,...
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Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation, Molecular Biology and Possible Control with Newly Designed Agents

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

Deadline for manuscript submissions: closed (31 December 2012) | Viewed by 79371

Special Issue Information

Dear Colleagues,

Multi-drug resistance of pathogenic bacterial clinical isolates is now known to be mainly due to over-expressed efflux pumps that result from therapy with antibiotics that is either ineffective or improperly administered [1]. The development of the MDR phenotype is thus problematic to therapy since resistance to the antibiotic initially used also bestows resistance to antibiotics of the same class and or other classes of antibiotics [1,2]. For the past two decades, much has been learned about the regulation and control of efflux pumps that render the clinical isolate with an MDR phenotype. Nevertheless, at this time, although many compounds have been identified to affect the activity of the over-expressed efflux pump of a given MDR bacterium and therefore render the antibiotic bacterium susceptible to antibiotics to which it was initially resistant, none have yet to reach the market as adjuncts to antibiotic therapy. The special issue of “Antibiotics” "Efflux pumps of multi-drug resistant pathogenic bacteria: Their genetic regulation, molecular biology and possible control with newly designed agents." will receive contributions from experts in the field of efflux pumps, their regulation and potential control with newly discovered agents from natural and chemically derived sources. We hope that those who are conducting research in this area will also submit their contributions for publication in this special issue.

1. Amaral, L.; Fanning, S.; Pagès, J.M. Efflux pumps of gram-negative bacteria: Genetic responses to stress and the modulation of their activity by pH, inhibitors, and phenothiazines. Adv. Enzymol. Relat. Areas Mol. Biol. 2011, 77, 61–108. Review.
2. Pagès, J.M.; Amaral, L. Fanning, S. An original deal for new molecule: Reversal of efflux pump activity, a rational strategy to combat Gram-negative resistant bacteria. Curr. Med. Chem. 2011, 18, 2969–2680.

Prof. Dr. Leonard Amaral
Guest Editor

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Published Papers (8 papers)

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Research

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575 KiB  
Article
Resistance to Antimicrobials Mediated by Efflux Pumps in Staphylococcus aureus
by Sofia S. Costa, Elisabete Junqueira, Cláudia Palma, Miguel Viveiros, José Melo-Cristino, Leonard Amaral and Isabel Couto
Antibiotics 2013, 2(1), 83-99; https://doi.org/10.3390/antibiotics2010083 - 13 Mar 2013
Cited by 35 | Viewed by 10281
Abstract
Resistance mediated by efflux has been recognized in Staphylococcus aureus in the last few decades, although its clinical relevance has only been recognized recently. The existence of only a few studies on the individual and overall contribution of efflux to resistance phenotypes associated [...] Read more.
Resistance mediated by efflux has been recognized in Staphylococcus aureus in the last few decades, although its clinical relevance has only been recognized recently. The existence of only a few studies on the individual and overall contribution of efflux to resistance phenotypes associated with the need of well-established methods to assess efflux activity in clinical isolates contributes greatly to the lack of solid knowledge of this mechanism in S. aureus. This study aims to provide information on approaches useful to the assessment and characterization of efflux activity, as well as contributing to our understanding of the role of efflux to phenotypes of antibiotic resistance and biocide tolerance in S. aureus clinical isolates. The results described show that efflux is an important contributor to fluoroquinolone resistance in S. aureus and suggest it as a major mechanism in the early stages of resistance development. We also show that efflux plays an important role on the reduced susceptibility to biocides in S. aureus, strengthening the importance of this long neglected resistance mechanism to the persistence and proliferation of antibiotic/biocide-resistant S. aureus in the hospital environment. Full article
(This article belongs to the Special Issue Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation, Molecular Biology and Possible Control with Newly Designed Agents)
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330 KiB  
Article
Virulence of Acinetobacter baumannii Exhibiting Phenotypic Heterogeneous Growth against Meropenem in a Murine Thigh Infection Model
by Evangelia Neou, George Michail, Athanassios Tsakris and Spyros Pournaras
Antibiotics 2013, 2(1), 73-82; https://doi.org/10.3390/antibiotics2010073 - 11 Mar 2013
Cited by 4 | Viewed by 6553
Abstract
Acinetobacter baumannii may exhibit phenotypic heterogeneous growth under exposure to antibiotics. We investigated the in vitro characteristics of A. baumannii isolates grown heterogeneously in the presence of meropenem and their virulence evaluated in experimental infections treated with meropenem. Five clinical A. baumannii isolates [...] Read more.
Acinetobacter baumannii may exhibit phenotypic heterogeneous growth under exposure to antibiotics. We investigated the in vitro characteristics of A. baumannii isolates grown heterogeneously in the presence of meropenem and their virulence evaluated in experimental infections treated with meropenem. Five clinical A. baumannii isolates and the respective heterogeneously grown subpopulations were tested by agar dilution minimum inhibitory concentration (MIC) testing, pulsed field gel electrophoresis (PFGE), population analysis using meropenem and growth curves. The virulence of isolates and the therapeutic efficacy of three meropenem dosing schemes was evaluated in a neutropenic murine thigh infection model. The clinical isolates were meropenem-susceptible (MICs 1 to 4 mg/liter) and exhibited three distinct PFGE patterns. In all clinical isolates, population analysis yielded heterogeneously grown colonies. After seven subcultures in antibiotic-free media, resistant MIC levels were retained in two isolates (heteroresistant), while three isolates were reversed to susceptible MICs (persisters). Clinical isolates and heterogeneous subpopulations had similar growth rates. The heterogeneously grown A. baumannii subpopulations had reduced virulence, killing considerably fewer animals than the respective clinical isolates without treatment. The meropenem treatment outcome was similar in infections caused by the clinical and the heterogeneous isolates, irrespective to their MICs. In vitro meropenem exposure induces phenotypic heterogeneous growth in A. baumannii. Compared with the parental clinical isolates, the heterogeneously grown subpopulations exhibited lower virulence, killing fewer mice and responding equally to meropenem treatment, despite their higher MICs. Full article
(This article belongs to the Special Issue Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation, Molecular Biology and Possible Control with Newly Designed Agents)
669 KiB  
Article
The Staphylococcus aureus Membrane Protein SA2056 Interacts with Peptidoglycan Synthesis Enzymes
by Chantal Quiblier, Agnieszka Luczak-Kadlubowska, Esther Holdener, Daniela Alborn, Tanja Schneider, Imke Wiedemann, Mariana G. Pinho, Hans-Georg Sahl, Susanne Rohrer, Brigitte Berger-Bächi and Maria Magdalena Senn
Antibiotics 2013, 2(1), 11-27; https://doi.org/10.3390/antibiotics2010011 - 22 Jan 2013
Cited by 1 | Viewed by 8787
Abstract
The yet uncharacterized membrane protein SA2056 belongs to the ubiquitous RND (Resistance-Nodulation-cell Division) family of transmembrane efflux transporters. The sa2056 gene is located downstream of femX, the gene encoding the essential, non-ribosomal peptidyl-transferase adding the first glycine in the staphylococcal cell wall [...] Read more.
The yet uncharacterized membrane protein SA2056 belongs to the ubiquitous RND (Resistance-Nodulation-cell Division) family of transmembrane efflux transporters. The sa2056 gene is located downstream of femX, the gene encoding the essential, non-ribosomal peptidyl-transferase adding the first glycine in the staphylococcal cell wall pentaglycine interpeptide. Due to its proximity to and weak co-transcription with femX, we assumed that sa2056 may somehow be involved in peptidoglycan synthesis. Specific antibodies against SA2056 showed that this protein is expressed during growth and present in the membrane fraction of cell preparations. Using a bacterial two hybrid system, SA2056 was shown to interact (i) with itself, (ii) with FemB, which adds glycines 4 and 5 to the peptidoglycan interpeptide and (iii) with the essential penicillin binding proteins, PBP1 and PBP2, required for cell division and incorporation of the peptidoglycan into the cell wall. Unexpectedly, deletion of sa2056 led to no phenotype regarding growth, antibiotic resistances or cell morphology; nor did sa2056 deletion in combination with femB inactivation alter b-lactam and lysostaphin sensitivity and resistance, respectively, pointing to possible redundancy in the cell wall synthesis pathway. These results suggest an accessory role of SA2056 in S. aureus peptidoglycan synthesis, broadening the range of biological functions of RND proteins. Full article
(This article belongs to the Special Issue Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation, Molecular Biology and Possible Control with Newly Designed Agents)
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Review

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377 KiB  
Review
Resistance-Nodulation-Division Multidrug Efflux Pumps in Gram-Negative Bacteria: Role in Virulence
by Dinesh M. Fernando and Ayush Kumar
Antibiotics 2013, 2(1), 163-181; https://doi.org/10.3390/antibiotics2010163 - 18 Mar 2013
Cited by 92 | Viewed by 11892
Abstract
Resistance-Nodulation-Division (RND) efflux pumps are one of the most important determinants of multidrug resistance (MDR) in Gram-negative bacteria. With an ever increasing number of Gram-negative clinical isolates exhibiting MDR phenotypes as a result of the activity of RND pumps, it is clear that [...] Read more.
Resistance-Nodulation-Division (RND) efflux pumps are one of the most important determinants of multidrug resistance (MDR) in Gram-negative bacteria. With an ever increasing number of Gram-negative clinical isolates exhibiting MDR phenotypes as a result of the activity of RND pumps, it is clear that the design of novel effective clinical strategies against such pathogens must be grounded in a better understanding of these pumps, including their physiological roles. To this end, recent evidence suggests that RND pumps play an important role in the virulence of Gram-negative pathogens. In this review, we discuss the important role RND efflux pumps play in different facets of virulence including colonization, evasion of host defense mechanisms, and biofilm formation. These studies provide key insights that may ultimately be applied towards strategies used in the design of effective therapeutics against MDR Gram negative bacterial pathogens. Full article
(This article belongs to the Special Issue Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation, Molecular Biology and Possible Control with Newly Designed Agents)
358 KiB  
Review
Role of Phenothiazines and Structurally Similar Compounds of Plant Origin in the Fight against Infections by Drug Resistant Bacteria
by Sujata G. Dastidar, Jette E. Kristiansen, Joseph Molnar and Leonard Amaral
Antibiotics 2013, 2(1), 58-72; https://doi.org/10.3390/antibiotics2010058 - 18 Feb 2013
Cited by 42 | Viewed by 8984
Abstract
Phenothiazines have their primary effects on the plasma membranes of prokaryotes and eukaryotes. Among the components of the prokaryotic plasma membrane affected are efflux pumps, their energy sources and energy providing enzymes, such as ATPase, and genes that regulate and code for the [...] Read more.
Phenothiazines have their primary effects on the plasma membranes of prokaryotes and eukaryotes. Among the components of the prokaryotic plasma membrane affected are efflux pumps, their energy sources and energy providing enzymes, such as ATPase, and genes that regulate and code for the permeability aspect of a bacterium. The response of multidrug and extensively drug resistant tuberculosis to phenothiazines shows an alternative therapy for the treatment of these dreaded diseases, which are claiming more and more lives every year throughout the world. Many phenothiazines have shown synergistic activity with several antibiotics thereby lowering the doses of antibiotics administered to patients suffering from specific bacterial infections. Trimeprazine is synergistic with trimethoprim. Flupenthixol (Fp) has been found to be synergistic with penicillin and chlorpromazine (CPZ); in addition, some antibiotics are also synergistic. Along with the antibacterial action described in this review, many phenothiazines possess plasmid curing activities, which render the bacterial carrier of the plasmid sensitive to antibiotics. Thus, simultaneous applications of a phenothiazine like TZ would not only act as an additional antibacterial agent but also would help to eliminate drug resistant plasmid from the infectious bacterial cells. Full article
(This article belongs to the Special Issue Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation, Molecular Biology and Possible Control with Newly Designed Agents)
464 KiB  
Review
Recent Advances in Multi-Drug Resistance (MDR) Efflux Pump Inhibitors of Gram-Positive Bacteria S. aureus
by Jadwiga Handzlik, Anna Matys and Katarzyna Kieć-Kononowicz
Antibiotics 2013, 2(1), 28-45; https://doi.org/10.3390/antibiotics2010028 - 5 Feb 2013
Cited by 128 | Viewed by 16574
Abstract
The paper focuses on recent achievements in the search for new chemical compounds able to inhibit multidrug resistance (MDR) mechanisms in Gram-positive pathogens. An analysis of the results of the search for new efflux pump inhibitors (EPIs) for Gram-positive bacteria, which have [...] Read more.
The paper focuses on recent achievements in the search for new chemical compounds able to inhibit multidrug resistance (MDR) mechanisms in Gram-positive pathogens. An analysis of the results of the search for new efflux pump inhibitors (EPIs) for Gram-positive bacteria, which have been performed over the last decade, indicates that almost all efforts are focused on the NorA (MFS) efflux pump in S. aureus. Considering the chemical structures of the NorA EPIs that have been identified, it can be observed that the most active agents belong to the families of compounds possessing conjugated double bonds, e.g., chalcones, piperine-like compounds, N-cinnamoylphenalkylamides or citral amide derivatives. Indole-, dihydronaphthyl-, 2-chloro-5-bromo-phenyl- or piperidine moieties seem to be profitable for the EPI properties, as well. These results, together with an increasing knowledge about a variety of efflux pumps that are involved in MDR of Gram-positive pathogens underline that further search for new EPIs should pay more attention to develop MDR efflux protein targets, including SMR, MATE, ABC or other members of the MFS family. Full article
(This article belongs to the Special Issue Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation, Molecular Biology and Possible Control with Newly Designed Agents)
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509 KiB  
Review
Multidrug Efflux Systems in Helicobacter cinaedi
by Yuji Morita, Junko Tomida and Yoshiaki Kawamura
Antibiotics 2012, 1(1), 29-43; https://doi.org/10.3390/antibiotics1010029 - 21 Nov 2012
Cited by 3 | Viewed by 8877
Abstract
Helicobacter cinaedi causes infections, such as bacteremia, diarrhea and cellulitis in mainly immunocompromised patients. This pathogen is often problematic to analyze, and insufficient information is available, because it grows slowly and poorly in subculture under a microaerobic atmosphere. The first-choice therapy to eradicate [...] Read more.
Helicobacter cinaedi causes infections, such as bacteremia, diarrhea and cellulitis in mainly immunocompromised patients. This pathogen is often problematic to analyze, and insufficient information is available, because it grows slowly and poorly in subculture under a microaerobic atmosphere. The first-choice therapy to eradicate H. cinaedi is antimicrobial chemotherapy; however, its use is linked to the development of resistance. Although we need to understand the antimicrobial resistance mechanisms of H. cinaedi, unfortunately, sufficient genetic tools for H. cinaedi have not yet been developed. In July 2012, the complete sequence of H. cinaedi strain PAGU 611, isolated from a case of human bacteremia, was announced. This strain possesses multidrug efflux systems, intrinsic antimicrobial resistance mechanisms and typical mutations in gyrA and the 23S rRNA gene, which are involved in acquired resistance to fluoroquinolones and macrolides, respectively. Here, we compare the organization and properties of the efflux systems of H. cinaedi with the multidrug efflux systems identified in other bacteria. Full article
(This article belongs to the Special Issue Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation, Molecular Biology and Possible Control with Newly Designed Agents)
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Other

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444 KiB  
Opinion
Photobactericides—A Local Option against Multi-Drug Resistant Bacteria
by Mark Wainwright and Leonard Amaral
Antibiotics 2013, 2(2), 182-190; https://doi.org/10.3390/antibiotics2020182 - 27 Mar 2013
Cited by 5 | Viewed by 6374
Abstract
The use of light-activated bactericidal agents—photobactericides—is suggested in local infection in order to conserve conventional antibacterials for more systemic disease. Local administration of a photobactericide such as methylene blue coupled with locally-targeted red light illumination ensures the production of non-specific reactive oxygen species [...] Read more.
The use of light-activated bactericidal agents—photobactericides—is suggested in local infection in order to conserve conventional antibacterials for more systemic disease. Local administration of a photobactericide such as methylene blue coupled with locally-targeted red light illumination ensures the production of non-specific reactive oxygen species and thus a rapid and localised antibacterial response, regardless of the conventional resistance status. To this end, the response of photobactericides to conventional resistance mechanisms, and their potential use in infection, is discussed. Full article
(This article belongs to the Special Issue Efflux Pumps of Multi-Drug Resistant Pathogenic Bacteria: Their Genetic Regulation, Molecular Biology and Possible Control with Newly Designed Agents)
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