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1.
Epidemiol Infect ; 150: e148, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35968840

RESUMO

Resistance to carbapenems in human pathogens is a growing clinical and public health concern. The carbapenems are in an antimicrobial class considered last-resort, they are used to treat human infections caused by multidrug-resistant Enterobacterales, and they are classified by the World Health Organization as 'High Priority Critically Important Antimicrobials'. The presence of carbapenem-resistant Enterobacterales (CREs) of animal-origin is of concern because targeted studies of Canadian retail seafood revealed the presence of carbapenem resistance in a small number of Enterobacterales isolates. To further investigate this issue, a risk profile was developed examining shrimp and salmon, the two most important seafood commodities consumed by Canadians and Escherichia coli, a member of the Enterobacterales order. Carbapenem-resistant E. coli (CREc) isolates have been identified in shrimp and other seafood products. Although carbapenem use in aquaculture has not been reported, several classes of antimicrobials are utilised globally and co-selection of antimicrobial-resistant microorganisms in an aquaculture setting is also of concern. CREs have been identified in retail seafood purchased in Canada and are currently thought to be uncommon. However, data concerning CRE or CREc occurrence and distribution in seafood are limited, and argue for implementation of ongoing or periodic surveillance.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Escherichia coli , Animais , Canadá/epidemiologia , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Salmão , Alimentos Marinhos , beta-Lactamases
2.
Epidemiol Infect ; 147: e296, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31679543

RESUMO

Codex published the 'Guidelines for Risk Analysis of Foodborne Antimicrobial Resistance' to standardise the approach for evaluating risk posed by foodborne antimicrobial-resistant bacteria. One of the first steps in the guidelines is to compile a risk profile, which provides the current state of knowledge regarding a food safety issue, describes risk management options and recommends next steps. In Canada, ceftiofur/ceftriaxone-resistant Salmonella enterica subsp. enterica serovar Heidelberg from poultry was identified as an antimicrobial resistance (AMR) food safety issue. The first objective of this article was to contextualise this food safety issue, using the risk profile format of the Codex Guidelines. A second objective was to evaluate the applicability of the Codex Guidelines. This risk profile indicated that ceftiofur/ceftriaxone-resistant S. Heidelberg (CSH) was commonly isolated from poultry and was associated with severe disease in humans. Ceftiofur use in poultry hatcheries temporally mirrored the prevalence of CSH from poultry meat at retail and from people with salmonellosis. The evidence was sufficient to indicate the need for risk management options, such as restricting the use of ceftiofur in poultry. The Codex Guidelines provided a useful approach to summarise data for decision-makers to evaluate an AMR food safety issue.


Assuntos
Antibacterianos/farmacologia , Ceftriaxona/farmacologia , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana , Microbiologia de Alimentos , Aves Domésticas/microbiologia , Salmonella enterica/efeitos dos fármacos , Animais , Canadá , Humanos , Testes de Sensibilidade Microbiana , Guias de Prática Clínica como Assunto , Medição de Risco , Gestão de Riscos , Intoxicação Alimentar por Salmonella/microbiologia , Intoxicação Alimentar por Salmonella/prevenção & controle , Salmonella enterica/isolamento & purificação
3.
Clin Microbiol Rev ; 28(2): 337-418, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25788514

RESUMO

The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.


Assuntos
Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos/fisiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Animais , Humanos
4.
J Am Vet Med Assoc ; 262(3): 303-312, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38295518

RESUMO

Antimicrobial resistance is a global One Health concern with critical implications for the health of humans, animals, and the environment. Phenotypic methods of bacterial culture and antimicrobial susceptibility testing remain the gold standards for the detection of antimicrobial resistance and appropriate patient care; however, genotypic-based methods, such as PCR, whole genome sequencing, and metagenomic sequencing, for detection of genes conferring antimicrobial resistance are increasingly available without inclusion of appropriate standards for quality or interpretation. Misleading test results may lead to inappropriate antimicrobial treatment and, in turn, poor patient outcomes and the potential for increased incidence of antimicrobial resistance. This article explores the current landscape of clinical and methodological aspects of antimicrobial susceptibility testing and genotypic antimicrobial resistance test methods. Additionally, it describes the limitations associated with employing genotypic-based test methods in the management of veterinary patients from a One Health perspective. The companion Currents in One Health by Maddock et al, AJVR, March 2024, addresses current and future needs for veterinary antimicrobial resistance research.


Assuntos
Anti-Infecciosos , Saúde Única , Humanos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/genética , Genótipo , Testes de Sensibilidade Microbiana/veterinária
5.
Am J Vet Res ; : 1-8, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38262139

RESUMO

Antimicrobial resistance (AMR) is a critical One Health concern with implications for human, animal, plant, and environmental health. Antimicrobial susceptibility testing (AST), antimicrobial resistance testing (ART), and surveillance practices must be harmonized across One Health sectors to ensure consistent detection and reporting practices. Veterinary diagnostic laboratory stewardship, clinical outcomes studies, and training for current and future generations of veterinarians and laboratorians are necessary to minimize the spread of AMR and move veterinary medicine forward into an age of better antimicrobial use practices. The purpose of this article is to describe current knowledge gaps present in the literature surrounding ART, AST, and clinical or surveillance applications of these methods and to suggest areas where AMR research can fill these knowledge gaps. The related Currents in One Health by Maddock et al, JAVMA, March 2024, addresses current limitations to the use of genotypic ART methods in clinical veterinary practice.

6.
Clin Infect Dis ; 57(5): 704-10, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23723195

RESUMO

Antibiotic resistance and associated genes are ubiquitous and ancient, with most genes that encode resistance in human pathogens having originated in bacteria from the natural environment (eg, ß-lactamases and fluoroquinolones resistance genes, such as qnr). The rapid evolution and spread of "new" antibiotic resistance genes has been enhanced by modern human activity and its influence on the environmental resistome. This highlights the importance of including the role of the environmental vectors, such as bacterial genetic diversity within soil and water, in resistance risk management. We need to take more steps to decrease the spread of resistance genes in environmental bacteria into human pathogens, to decrease the spread of resistant bacteria to people and animals via foodstuffs, wastes and water, and to minimize the levels of antibiotics and antibiotic-resistant bacteria introduced into the environment. Reducing this risk must include improved management of waste containing antibiotic residues and antibiotic-resistant microorganisms.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/veterinária , Farmacorresistência Bacteriana , Animais , Infecções Bacterianas/microbiologia , Uso de Medicamentos/normas , Transferência Genética Horizontal , Humanos , Seleção Genética , Purificação da Água/métodos
7.
Emerg Infect Dis ; 19(7)2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23764294

RESUMO

The clinical failure of antimicrobial drugs that were previously effective in controlling infectious disease is a tragedy of increasing magnitude that gravely affects human health. This resistance by pathogens is often the endpoint of an evolutionary process that began billions of years ago in non-disease-causing microorganisms. This environmental resistome, its mobilization, and the conditions that facilitate its entry into human pathogens are at the heart of the current public health crisis in antibiotic resistance. Understanding the origins, evolution, and mechanisms of transfer of resistance elements is vital to our ability to adequately address this public health issue.


Assuntos
Antibacterianos/farmacologia , Bactérias/genética , Farmacorresistência Bacteriana/genética , Poluentes Ambientais/farmacologia , Bactérias/efeitos dos fármacos , Evolução Molecular , Transferência Genética Horizontal , Genes Bacterianos , Humanos , Microbiologia do Solo
8.
Eur J Pharmacol ; 960: 176128, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37866747

RESUMO

Programmed cell death receptor/ligand 1 (PD-1/PD-L1) blockade therapy for various cancers induces itch. However, few studies have evaluated the mechanism underlying PD-1/PD-L1 inhibitor-induced itch. This study aimed to establish and evaluate a mouse model of acute itch induced by PD-1/PD-L1 inhibitors and to explore the role of the PD-1/PD-L1 pathway in chronic itch. The intradermal injection of the PD-1/PD-L1 small molecule inhibitors, or anti-PD-1/PD-L1 antibodies in the nape of the neck in the mice elicited intense spontaneous scratches. The model was evaluated using pharmacological methods. The number of scratches was reduced by naloxone but not by antihistamines or the transient receptor potential (TRP) channel inhibitor. Moreover, the PD-1 receptor was detected in the spinal cord of the mouse models of chronic itch that exhibited acetone, diethyl ether, and water (AEW)-induced dry skin, imiquimod-induced psoriasis, and 1-fluoro-2,4-dinitrobenzene (DNFB)-induced allergic contact dermatitis. Intrathecal PD-L1 (1 µg, 4 times a week for 1 week) suppressed the activation of the microglia in the spinal dorsal horn to relieve the chronic itch that was elicited by imiquimod-induced psoriasis and DNFB-induced allergic contact dermatitis. Although the activation of the microglia in the spinal dorsal horn was not detected in the AEW-treated mice, intrathecal PD-L1 still reduced the number of scratches that were elicited by AEW. Our findings suggest that histamine receptor inhibitors or TRP channel inhibitors have limited effects on PD-1/PD-L1 inhibitor-induced itch and that spinal PD-1 is important for the spinal activation of the microglia, which may underlie chronic itch.


Assuntos
Dermatite Alérgica de Contato , Psoríase , Animais , Camundongos , Receptor de Morte Celular Programada 1 , Dinitrofluorbenzeno/efeitos adversos , Antígeno B7-H1 , Imiquimode/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Prurido/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Dermatite Alérgica de Contato/tratamento farmacológico , Modelos Animais de Doenças , Psoríase/tratamento farmacológico , Camundongos Endogâmicos C57BL
9.
Antibiotics (Basel) ; 12(9)2023 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-37760708

RESUMO

The extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales (ESBL-EB) encompass several important human pathogens and are found on the World Health Organization (WHO) priority pathogens list of antibiotic-resistant bacteria. They are a group of organisms which demonstrate resistance to third-generation cephalosporins (3GC) and their presence has been documented worldwide, including in aquaculture and the aquatic environment. This risk profile was developed following the Codex Guidelines for Risk Analysis of Foodborne Antimicrobial Resistance with the objectives of describing the current state of knowledge of ESBL-EB in relation to retail shrimp and salmon available to consumers in Canada, the primary aquacultured species consumed in Canada. The risk profile found that Enterobacterales and ESBL-EB have been found in multiple aquatic environments, as well as multiple host species and production levels. Although the information available did not permit the conclusion as to whether there is a human health risk related to ESBLs in Enterobacterales in salmon and shrimp available for consumption by Canadians, ESBL-EB in imported seafood available at the retail level in Canada have been found. Surveillance activities to detect ESBL-EB in seafood are needed; salmon and shrimp could be used in initial surveillance activities, representing domestic and imported products.

10.
Front Endocrinol (Lausanne) ; 13: 905703, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36034435

RESUMO

Objectives: The progressive impairment of ß-cell function results in prolonged deterioration in patients with type 2 diabetes mellitus (T2DM). Interestingly, the finding on pancreatitis secondary to renal injury suggests that potential communication exists between kidney and pancreas. Therefore, we aimed to investigate cell division cycle 42 (Cdc42)-mediated podocyte apoptosis and its effect on insulin secretion in islet ß-cells. Methods: Type 2 diabetic nephropathy mouse models were established to identify the expression of Cdc42 in podocytes by immunohistochemistry. An in vitro co-culture of mouse podocyte MPC5 and ß-TC6 cells was preliminarily established. Subsequently, podocyte apoptosis induced by high glucose and Cdc42 was detected by TUNEL staining and western blotting. In addition, the JNK pathway was examined to determine the mechanism of apoptosis in MPC5 cells. Finally, insulin secretion and expression in ß-TC6 cells as well as malondialdehyde (MDA) and superoxide dismutase (SOD) levels in both cell types were examined after the regulation of Cdc42 in MPC5 cells. Results: Cdc42 was highly expressed in the podocytes of diabetic nephropathy mice. Exposure to 25 mM glucose for 48 h induced a significant upregulation of Cdc42, Bax, and cleaved caspase-3 as well as a decreased Bcl-2 expression. In addition, marked apoptosis of MPC5 cells was observed compared to normal glucose treatment. After transfection with Cdc42 plasmid, apoptosis of MPC5 cells was enhanced with an increased expression of p-JNK, whereas inhibition of Cdc42 significantly alleviated podocyte apoptosis accompanied by a downregulation of p-JNK. The glucose-stimulated insulin secretion level of ß-TC6 cells decreased after the upregulation of Cdc42 in MPC5 cells. Immunofluorescence staining for insulin showed that co-culture with MPC5 cells carrying the Cdc42 plasmid significantly reduced insulin expression, whereas inhibition of Cdc42 in MPC5 cells alleviated the above-mentioned abnormality of ß-TC6 cells. The expression of Cdc42 and p-p38 in ß-TC6 cells increased following the upregulation of Cdc42 in MPC5 cells; this was concurrent with augmented MDA levels and decreased SOD activity. The opposite result was observed for Cdc42 knockdown in MPC5 cells. Conclusions: Cdc42 in podocytes plays a crucial role in insulin secretion by ß-cells, which may provide a new therapeutic target to prevent the vicious cycle of ß-cell dysfunction in T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insulinas , Podócitos , Proteína cdc42 de Ligação ao GTP/metabolismo , Animais , Apoptose , Glucose , Secreção de Insulina , Camundongos , Superóxido Dismutase , Regulação para Cima
11.
Antibiotics (Basel) ; 11(2)2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35203828

RESUMO

Surveillance of antimicrobial use (AMU) and antimicrobial resistance (AMR) is a core component of the 2017 Pan-Canadian Framework for Action. There are existing AMU and AMR surveillance systems in Canada, but some stakeholders are interested in developing their own AMU monitoring/surveillance systems. It was recognized that the establishment of core (minimum) AMU data elements, as is necessary for policy or intervention development, would inform the development of practical and sustainable AMU surveillance capacity across food animal sectors in Canada. The Canadian Animal Health Surveillance System (CAHSS) AMU Network was established as a multisectoral working group to explore the possibility of harmonizing data inputs and outputs. There was a consensus that a minimum AMU dataset for AMU surveillance (MDS-AMU-surv) should be developed to guide interested parties in initiating AMU data collection. This multisectoral collaboration is an example of how consultative consensus building across relevant sectors can contribute to the development of harmonized approaches to AMU data collection and reporting and ultimately improve AMU stewardship. The MDS-AMU-surv could be used as a starting point for the progressive development or strengthening of AMU surveillance programs, and the collaborative work could serve as a model for addressing AMR and other shared threats at the human-animal-environment interface.

12.
Int J Antimicrob Agents ; 33(1): 27-32, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18790612

RESUMO

Of 112 non-repetitive clinical isolates of Acinetobacter baumannii-Acinetobacter calcoaceticus complex, 80% were resistant to a variety of structurally unrelated antimicrobials although all isolates were susceptible to minocycline and polymyxin. Resistance to carbapenems occurred in 8% of the isolates. The presence of adeSR-adeABC, adeDE and adeIJK drug efflux system genes and class 1 integron genes (integrase gene int1) was assessed by polymerase chain reaction (PCR) in relation to the susceptibility of the isolates to 20 antimicrobials. The majority of isolates (75%) with high levels of multidrug resistance were positive for adeSR-adeABC and adeIJK as well as int1 and thus belong to A. baumannii (i.e. genomospecies 2). Positive adeE was only observed in adeSR-adeABC/adeIJK/int1-negative isolates (8%; likely belonging to Acinetobacter genomospecies 3) that were relatively susceptible to several agents, and adeE expression was undetectable. The results reveal a possible association between adeABC/adeIJK and int1 in multidrug-resistant isolates of A. baumannii. In addition, differential distribution of the resistance-nodulation-cell division (RND) genes can likely be used as indicators for differentiating Acinetobacter species.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter calcoaceticus/efeitos dos fármacos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Integrons/genética , Proteínas de Membrana Transportadoras/genética , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/classificação , Acinetobacter baumannii/genética , Acinetobacter baumannii/metabolismo , Acinetobacter calcoaceticus/classificação , Acinetobacter calcoaceticus/genética , Acinetobacter calcoaceticus/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Humanos , Integrons/fisiologia , Proteínas de Membrana Transportadoras/metabolismo , Testes de Sensibilidade Microbiana
13.
Vet Microbiol ; 121(3-4): 197-214, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17306475

RESUMO

beta-Lactams are among the most clinically important antimicrobials in both human and veterinary medicine. Bacterial resistance to beta-lactams has been increasingly observed in bacteria, including those of animal origin. The mechanisms of beta-lactam resistance include inaccessibility of the drugs to their target, target alterations and/or inactivation of the drugs by beta-lactamases. The latter contributes predominantly to beta-lactam resistance in Gram-negative bacteria. A variety of beta-lactamases have been identified in bacteria derived from food-producing and companion animals and may further serve as a reservoir for beta-lactamase-producing bacteria in humans. While this review mainly describes beta-lactamases from animal-derived Escherichia coli and Salmonella spp., beta-lactamases from animal-derived Campylobacter spp., Enterococcus spp., Staphylococcus spp. and other pathogens are also discussed. Of particular concern are the increasingly-isolated plasmid-encoded AmpC-type CMY and extended-spectrum CTX-M beta-lactamases, which mediate acquired resistance to extended-spectrum beta-lactams. The genes encoding these enzymes often coexist with other antimicrobial resistance determinants and can also be associated with transposons/integrons, increasing the potential enrichment of multidrug resistant bacteria by multiple antimicrobial agents as well as dissemination of the resistance determinants among bacterial species. Characterization of beta-lactam-resistant animal-derived bacteria warrants further investigation of the type and distribution of beta-lactamases in bacteria of animal origin and their potential impact on human medicine.


Assuntos
Doenças dos Animais/microbiologia , Infecções por Escherichia coli/veterinária , Escherichia coli/enzimologia , Salmonelose Animal/microbiologia , Salmonella/enzimologia , Resistência beta-Lactâmica , beta-Lactamases/metabolismo , beta-Lactamas/farmacologia , Doenças dos Animais/tratamento farmacológico , Animais , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Humanos , Salmonella/efeitos dos fármacos , Salmonelose Animal/tratamento farmacológico , beta-Lactamas/uso terapêutico
14.
Int J Antimicrob Agents ; 25(6): 453-63, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15890498

RESUMO

Bacterial resistance to quinolones/fluoroquinolones has emerged rapidly and such resistance has traditionally been attributed to the chromosomally mediated mechanisms that alter the quinolone targets (i.e. DNA gyrase and topoisomerase IV) and/or overproduce multidrug resistance efflux pumps. However, the discovery of the plasmid-borne quinolone resistance determinant, named qnr, has substantially broadened our horizon on the molecular mechanisms of quinolone resistance. Several recent reports of Qnr or its homologues encoded by transferable plasmids in Gram-negative bacteria isolated worldwide highlight the significance of the emerging plasmid-mediated mechanism(s). This also alerts us to the potential rapid dissemination of quinolone resistance determinants. Qnr belongs to the pentapeptide repeat family and protects DNA gyrase from the action of quinolone agents including the newer fluoroquinolones. This protection interplays with chromosomal mechanisms to raise significantly the resistance levels. The qnr-bearing strains generate quinolone-resistant mutants at a much higher frequency than those qnr-free strains. Furthermore, the qnr-plasmids are integron-associated and carry multiple resistance determinants providing resistance to several classes of antimicrobials including beta-lactams and aminoglycosides. The high quinolone resistance rates in Escherichia coli are used to address issues of quinolone resistance, and possible strategies for minimising quinolone resistance are discussed.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana , Plasmídeos , Quinolonas/farmacologia , Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli/fisiologia , Integrons
15.
Drugs ; 64(2): 159-204, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14717618

RESUMO

Drug resistance in bacteria, and especially resistance to multiple antibacterials, has attracted much attention in recent years. In addition to the well known mechanisms, such as inactivation of drugs and alteration of targets, active efflux is now known to play a major role in the resistance of many species to antibacterials. Drug-specific efflux (e.g. that of tetracycline) has been recognised as the major mechanism of resistance to this drug in Gram-negative bacteria. In addition, we now recognise that multidrug efflux pumps are becoming increasingly important. Such pumps play major roles in the antiseptic resistance of Staphylococcus aureus, and fluoroquinolone resistance of S. aureus and Streptococcus pneumoniae. Multidrug pumps, often with very wide substrate specificity, are not only essential for the intrinsic resistance of many Gram-negative bacteria but also produce elevated levels of resistance when overexpressed. Paradoxically, 'advanced' agents for which resistance is unlikely to be caused by traditional mechanisms, such as fluoroquinolones and beta-lactams of the latest generations, are likely to select for overproduction mutants of these pumps and make the bacteria resistant in one step to practically all classes of antibacterial agents. Such overproduction mutants are also selected for by the use of antiseptics and biocides, increasingly incorporated into consumer products, and this is also of major concern. We can consider efflux pumps as potentially effective antibacterial targets. Inhibition of efflux pumps by an efflux pump inhibitor would restore the activity of an agent subject to efflux. An alternative approach is to develop antibacterials that would bypass the action of efflux pumps.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/fisiologia , Proteínas de Membrana Transportadoras/metabolismo , Farmacorresistência Bacteriana Múltipla/genética , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/genética , Bactérias Gram-Negativas/fisiologia , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/genética , Bactérias Gram-Positivas/fisiologia
16.
Drugs ; 69(12): 1555-623, 2009 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-19678712

RESUMO

Drug efflux pumps play a key role in drug resistance and also serve other functions in bacteria. There has been a growing list of multidrug and drug-specific efflux pumps characterized from bacteria of human, animal, plant and environmental origins. These pumps are mostly encoded on the chromosome, although they can also be plasmid-encoded. A previous article in this journal provided a comprehensive review regarding efflux-mediated drug resistance in bacteria. In the past 5 years, significant progress has been achieved in further understanding of drug resistance-related efflux transporters and this review focuses on the latest studies in this field since 2003. This has been demonstrated in multiple aspects that include but are not limited to: further molecular and biochemical characterization of the known drug efflux pumps and identification of novel drug efflux pumps; structural elucidation of the transport mechanisms of drug transporters; regulatory mechanisms of drug efflux pumps; determining the role of the drug efflux pumps in other functions such as stress responses, virulence and cell communication; and development of efflux pump inhibitors. Overall, the multifaceted implications of drug efflux transporters warrant novel strategies to combat multidrug resistance in bacteria.


Assuntos
Antibacterianos/metabolismo , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Farmacorresistência Bacteriana/fisiologia , Animais , Biofilmes/efeitos dos fármacos , Proteínas de Transporte/biossíntese , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/metabolismo , Humanos , Mycobacterium/efeitos dos fármacos , Mycobacterium/metabolismo
17.
J Bacteriol ; 186(10): 2973-83, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15126457

RESUMO

The membrane fusion protein (MFP) component, MexA, of the MexAB-OprM multidrug efflux system of P. aeruginosa is proposed to link the inner (MexB) and outer (OprM) membrane components of this pump as a probable oligomer. A cross-linking approach confirmed the in vivo interaction of MexA and MexB, while a LexA-based assay for assessing protein-protein interaction similarly confirmed MexA multimerization. Mutations compromising the MexA contribution to antibiotic resistance but yielding wild-type levels of MexA were recovered and shown to map to two distinct regions within the N- and C-terminal halves of the protein. Most of the N-terminal mutations occurred at residues that are highly conserved in the MFP family (P68, G72, L91, A108, L110, and V129), consistent with these playing roles in a common feature of these proteins (e.g., oligomerization). In contrast, the majority of the C-terminal mutations occurred at residues poorly conserved in the MFP family (V264, N270, H279, V286, and G297), with many mapping to a region of MexA that corresponds to a region in the related MFP of Escherichia coli, AcrA, that is implicated in binding to its RND component, AcrB (C. A. Elkins and H. Nikaido, J. Bacteriol. 185:5349-5356, 2003). Given the noted specificity of MFP-RND interaction in this family of pumps, residues unique to MexA may well be important for and define the MexA interaction with its RND component, MexB. Still, all but one of the MexA mutations studied compromised MexA-MexB association, suggesting that native structure and/or proper assembly of the protein may be necessary for this.


Assuntos
Proteínas da Membrana Bacteriana Externa/química , Proteínas de Transporte/química , Proteínas de Membrana Transportadoras/química , Pseudomonas aeruginosa/química , Sequência de Aminoácidos , Sequência Conservada , Dimerização , Farmacorresistência Bacteriana , Dados de Sequência Molecular , Mutação , Pseudomonas aeruginosa/genética
18.
Antimicrob Agents Chemother ; 48(7): 2415-23, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15215089

RESUMO

The Mycobacterium smegmatis genome contains many genes encoding putative drug efflux pumps. Yet with the exception of lfrA, it is not clear whether these genes contribute to the intrinsic drug resistance of this organism. We showed first by reverse transcription (RT)-PCR that several of these genes, including lfrA as well as the homologues of Mycobacterium tuberculosis Rv1145, Rv1146, Rv1877, Rv2846c (efpA), and Rv3065 (mmr and emrE), were expressed at detectable levels in the strain mc(2)155. Null mutants each carrying an in-frame deletion of these genes were then constructed in M. smegmatis. The deletions of the lfrA gene or mmr homologue rendered the mutant more susceptible to multiple drugs such as fluoroquinolones, ethidium bromide, and acriflavine (two- to eightfold decrease in MICs). The deletion of the efpA homologue also produced increased susceptibility to these agents but unexpectedly also resulted in decreased susceptibility to rifamycins, isoniazid, and chloramphenicol (two- to fourfold increase in MICs). Deletion of the Rv1877 homologue produced some increased susceptibility to ethidium bromide, acriflavine, and erythromycin. The upstream region of lfrA contained a gene encoding a putative TetR family transcriptional repressor, dubbed LfrR. The deletion of lfrR elevated the expression of lfrA and produced higher resistance to multiple drugs. Multidrug-resistant single-step mutants, independent of LfrA and attributed to a yet-unidentified drug efflux pump (here called LfrX), were selected in vitro and showed decreased accumulation of norfloxacin, ethidium bromide, and acriflavine in intact cells. Finally, use of isogenic beta-lactamase-deficient strains showed the contribution of LfrA and LfrX to resistance to certain beta-lactams in M. smegmatis.


Assuntos
Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/metabolismo , Acriflavina/metabolismo , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Farmacorresistência Bacteriana Múltipla , Etídio/metabolismo , Corantes Fluorescentes/metabolismo , Deleção de Genes , Genes Bacterianos/genética , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/genética , Norfloxacino/metabolismo , Permeabilidade , Plasmídeos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética , beta-Lactamases/metabolismo
19.
Antimicrob Agents Chemother ; 46(2): 333-43, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11796339

RESUMO

A homologue of the mexAB-oprM multidrug efflux operon of Pseudomonas aeruginosa, smeABC, was cloned from Stenotrophomonas maltophilia by using, as a probe, a PCR product amplified from this organism with primers based on the mexB sequence. The smeABC genes were hyperexpressed in a mutant strain displaying resistance to several antimicrobials, including aminoglycosides, beta-lactams, and fluoroquinolones. Deletions in smeC but not smeB compromised this resistance, suggesting that SmeC contributed to the multidrug resistance of the mutant as part of another, as-yet-unidentified multidrug efflux system. Consistent with SmeC functioning independently of SmeAB, a promoter activity was identified upstream of smeC. Upstream of the smeABC genes, a putative two-gene operon, smeSR, encoding homologues of bacterial two-component regulatory systems was identified. The cloned smeR gene activated expression of a smeA-lacZ fusion, indicating that SmeR positively regulates expression of the smeABC genes. Consistent with this, the multidrug resistance of the SmeABC-hyperexpressing mutant was compromised by deletion of smeR. Intriguingly, SmeC expression in S. maltophilia paralleled a beta-lactamase activity provided by a C-terminally truncated L2 enzyme, which was apparently responsible for the beta-lactam resistance of the SmeABC-hyperexpressing mutant. This represents the first report of coregulation of an efflux resistance determinant and a beta-lactamase.


Assuntos
Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Bactérias/genética , Resistência a Múltiplos Medicamentos/genética , Regulação Bacteriana da Expressão Gênica , Óperon , Stenotrophomonas maltophilia/genética , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Bactérias/metabolismo , Transporte Biológico , Clonagem Molecular , Análise de Sequência de DNA , Stenotrophomonas maltophilia/metabolismo , beta-Lactamases/metabolismo
20.
Antimicrob Agents Chemother ; 47(1): 27-33, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12499164

RESUMO

Of the six putative small multidrug resistance (SMR) family proteins of Pseudomonas aeruginosa, a protein encoded by the PA4990 gene (emrE(Pae)) shows the highest identity to the well-characterized EmrE efflux transporter of Escherichia coli. Reverse transcription-PCR confirmed the expression of emrE(Pae) in the wild-type strain of P. aeruginosa. Using isogenic emrE(Pae), mexAB-oprM, and/or mexB deletion mutants, the contributions of the EmrE protein and the MexAB-OprM efflux system to drug resistance in P. aeruginosa were assessed by a drug susceptibility test carried out in a low-ionic-strength medium, Difco nutrient broth. We found that EmrE(Pae) contributed to intrinsic resistance not only to ethidium bromide and acriflavine but also to aminoglycosides. In this low-ionic-strength medium, MexAB-OprM was also shown to contribute to aminoglycoside resistance, presumably via active efflux. Aminoglycoside resistance caused by these two pumps could not be demonstrated in high-ionic-strength media, such as Luria broth or Mueller-Hinton broth. The EmrE-dependent efflux of ethidium bromide was confirmed by a continuous fluorescence assay.


Assuntos
Antibacterianos/farmacologia , Antiporters/genética , Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Transporte/genética , Farmacorresistência Bacteriana/genética , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Pseudomonas aeruginosa/genética , Sequência de Aminoácidos , Aminoglicosídeos , Antiporters/efeitos dos fármacos , Proteínas da Membrana Bacteriana Externa/efeitos dos fármacos , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Escherichia coli , Proteínas de Membrana/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Plasmídeos , Pseudomonas aeruginosa/efeitos dos fármacos
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