RESUMO
(1) Background: Acinetobacter baumannii has become the most important pathogen responsible for nosocomial infections in health systems. It expresses several resistance mechanisms, including the production of ß-lactamases, changes in the cell membrane, and the expression of efflux pumps. (2) Methods: A. baumannii was detected by PCR amplification of the blaOXA-51-like gene. Antimicrobial susceptibility to fluoroquinolones and aminoglycosides was assessed using the broth microdilution technique according to 2018 CLSI guidelines. Efflux pump system activity was assessed by the addition of a phenylalanine-arginine beta-naphthylamide (PAßN) inhibitor. (3) Results: A total of nineteen A. baumannii clinical isolates were included in the study. In an overall analysis, in the presence of PAßN, amikacin susceptibility rates changed from 84.2% to 100%; regarding tobramycin, they changed from 68.4% to 84.2%; for nalidixic acid, they changed from 73.7% to 79.0%; as per ciprofloxacin, they changed from 68.4% to 73.7%; and, for levofloxacin, they stayed as 79.0% in both groups. (4) Conclusions: The addition of PAßN demonstrated a decrease in the rates of resistance to antimicrobials from the family of quinolones and aminoglycosides. Efflux pumps play an important role in the emergence of multidrug-resistant A. baumannii strains, and their inhibition may be useful as adjunctive therapy against this pathogen.
RESUMO
The rising of diseases caused by multidrug-resistant bacteria has encouraged researchers to explore more antimicrobial substances, as well as chemicals capable of potentiating the action of existing ones against multidrug-resistant bacteria. Anacardium occidentale produces a fruit known as cashew nut, filled with a dark, almost black, caustic, and flammable liquid called cashew nutshell liquid (CNSL). The goal of the study was to evaluate the intrinsic antimicrobial activity of the major compounds present in CNSL, called anacardic acids (AA), as well as their possible modulatory action as an adjuvant of Norfloxacin against a Staphylococcus aureus strain overproducing the NorA efflux pump (SA1199B). Microdilution assays were performed to determine the minimum inhibitory concentration (MIC) of AA against different microbial species. Norfloxacin and Ethidium Bromide (EtBr) resistance modulation assays were performed in the presence or absence of AA against SA1199-B. AA showed antimicrobial activity against Gram-positive bacterial strains tested but no activity against Gram-negative bacteria or yeast strains. At subinhibitory concentration, AA reduced the MIC values for Norfloxacin and EtBr against the SA1199-B strain. Furthermore, AA increased the intracellular accumulation of EtBr in this NorA overproducer strain, indicating that AA are NorA inhibitors. Docking analysis showed that AA probably modulates Norfloxacin efflux by spatial impediment at the same binding site of NorA.
Assuntos
Anacardium , Infecções Estafilocócicas , Norfloxacino/farmacologia , Antibacterianos/farmacologia , Staphylococcus aureus , Anacardium/metabolismo , Ácidos Anacárdicos/farmacologia , Ácidos Anacárdicos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Infecções Estafilocócicas/microbiologia , Etídio/metabolismo , Etídio/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
Antibiotic resistance can be characterized, in biochemical terms, as an antibiotic's inability to reach its bacterial target at a concentration that was previously effective. Microbial resistance to different agents can be intrinsic or acquired. Intrinsic resistance occurs due to inherent functional or structural characteristics of the bacteria, such as antibiotic-inactivating enzymes, nonspecific efflux pumps, and permeability barriers. On the other hand, bacteria can acquire resistance mechanisms via horizontal gene transfer in mobile genetic elements such as plasmids. Acquired resistance mechanisms include another category of efflux pumps with more specific substrates, which are plasmid-encoded. Efflux pumps are considered one of the main mechanisms of bacterial resistance to antibiotics and biocides, presenting themselves as integral membrane transporters. They are essential in both bacterial physiology and defense and are responsible for exporting structurally diverse substrates, falling into the following main families: ATP-binding cassette (ABC), multidrug and toxic compound extrusion (MATE), major facilitator superfamily (MFS), small multidrug resistance (SMR) and resistance-nodulation-cell division (RND). The Efflux pumps NorA and Tet(K) of the MFS family, MepA of the MATE family, and MsrA of the ABC family are some examples of specific efflux pumps that act in the extrusion of antibiotics. In this review, we address bacterial efflux pump inhibitors (EPIs), including 1,8-naphthyridine sulfonamide derivatives, given the pre-existing knowledge about the chemical characteristics that favor their biological activity. The modification and emergence of resistance to new EPIs justify further research on this theme, aiming to develop efficient compounds for clinical use.
Assuntos
Proteínas de Bactérias , Staphylococcus aureus , Humanos , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Sulfonamidas/farmacologia , Bactérias , Antibacterianos/farmacologia , Sulfanilamida/farmacologia , Naftiridinas/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
Undue exposure to antimicrobials has led to the acquisition and development of sophisticated bacterial resistance mechanisms, such as efflux pumps, which are able to expel or reduce the intracellular concentration of various antibiotics, making them ineffective. Therefore, inhibiting this mechanism is a promising way to minimize the phenomenon of resistance in bacteria. In this sense, the present study sought to evaluate the activity of the Carvacrol (CAR) and Thymol (THY) terpenes as possible Efflux Pump Inhibitors (EPIs), by determining the Minimum Inhibitory Concentration (MIC) and the association of these compounds in subinhibitory concentrations with the antibiotic Norfloxacin and with Ethidium Bromide (EtBr) against strains SA-1199 (wild-type) and SA-1199B (overexpresses NorA) of Staphylococcus aureus. In order to verify the interaction of the terpenes with the NorA efflux protein, an in silico molecular modeling study was carried out. The assays used to obtain the MIC of CAR and THY were performed by broth microdilution, while the Efflux Pump inhibitory test was performed by the MIC modification method of the antibiotic Norfloxacin and EtBr. docking was performed using the Molegro Virtual Docker (MVD) program. The results of the study revealed that CAR and THY have moderate bacterial activity and are capable of reducing the MIC of Norfloxacin antibiotic and EtBr in strains of S. aureus carrying the NorA efflux pump. The docking results showed that these terpenes act as possible competitive NorA inhibitors and can be investigated as adjuvants in combined therapies aimed at reducing antibiotic resistance.
Assuntos
Cimenos/uso terapêutico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Norfloxacino/uso terapêutico , Staphylococcus aureus/efeitos dos fármacos , Timol/uso terapêutico , Cimenos/farmacologia , Norfloxacino/farmacologia , Timol/farmacologiaRESUMO
Infectious diseases caused by multidrug-resistant microorganisms has increased in the last years. Piper species have been reported as a natural source of phytochemicals that can help in combating fungal and bacterial infections. This study had as objectives characterize the chemical composition of the essential oil from Piper caldense (EOPC), evaluate its potential antimicrobial activity, and investigate the synergistic effect with Norfloxacin against multidrug-resistant S. aureus overproducing efflux pumps, as well as, verify the EOPC ability to inhibit the Candida albicans filamentation. EOPC was extracted by hydrodistillation, and the chemical constituents were identified by gas chromatography, allowing the identification of 24 compounds (91.9%) classified as hydrocarbon sesquiterpenes (49.6%) and oxygenated sesquiterpenes (39.5%). Antimicrobial tests were performed using a 96-well plate microdilution method against C. albicans ATCC 10231, Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923 standard strains, as well as against multidrug-resistant strains S. aureus SA1199B (overexpressing norA gene), S. aureus K2068 (overexpressing mepA gene) and S. aureus K4100 (overexpressing qacC gene). The oil showed activity against C. albicans ATCC 10231 (≥ 512 µg/mL) and was able to inhibit hyphae formation, an important mechanism of virulence of C. albicans. On the other hand, EOPC was inactive against all bacterial strains tested (≤ 1,024 µg mL). However, when combined with Norfloxacin at subinhibitory concentration EOPC reduced the Norfloxacin and Ethidium bromide MIC values against S. aureus strains SA1199B, K2068 and K4100. These results indicate that EOPC is a source of phytochemicals acting as NorA, MepA and QacC inhibitors.
Assuntos
Proteínas de Bactérias , Staphylococcus aureus Resistente à Meticilina , Norfloxacino , Óleos Voláteis , Piper , Staphylococcus aureus , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Norfloxacino/química , Norfloxacino/farmacologia , Óleos Voláteis/farmacologia , Piper/química , Piper/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genéticaRESUMO
This study was focused on elucidating inhibition of antibiotic efflux mechanism of cadmium adapted (CdA) Salmonella Typhi Ty2 cells. Herein, upregulated expression of efflux genes (acrB, tolC) and their regulators (soxS, marA) was observed in CdA Ty2 cells by qRT-PCR. The pathogen further elevated the expression of these genes even in the presence of three efflux pump inhibitors (EPIs), i.e., Phe-Arg-ß-naphthylamide, 1-(1-naphthyl-methyl)piperazine, and 5-hydroxy-2-methyl-1,4-naphthoquinone, perhaps by sensing the pressure of the latter in addition to cadmium stress. Interaction of different EPIs with efflux pumps of CdA Ty2 cells was confirmed using ethidium bromide (EtBr) accumulation and efflux assay. All the EPIs could cause retention of EtBr which was indicated by increased fluorescence units. Considering this potential of EPIs, retention of antibiotics was evaluated in CdA Ty2 cells wherein EPIs were used in combination with selected antibiotics (instead of EtBr). A decrease in the effective concentration of antibiotics was observed. This was further validated using the clinical isolates. The data revealed the efficiency of EPIs as they could inhibit the efflux potential of even the overexpressed efflux pumps. Thus, combination of EPI(s)-antibiotics may be exploited in future as one of the strategies for combating metal induced antibiotic resistance.
Assuntos
Antibacterianos , Cádmio , Farmacorresistência Bacteriana Múltipla , Piperazina , Salmonella typhi , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Testes de Sensibilidade Microbiana , Piperazina/farmacologia , Salmonella typhi/efeitos dos fármacos , Salmonella typhi/genéticaRESUMO
AIMS: This study aimed to investigate the potential of limonene as an efflux pump (EP) inhibitor in Staphylococcus aureus strains, RN-4220 and IS-58, which carry EPs for erythromycin (MrsA) and tetracycline (TetK), respectively. BACKGROUND: The evolution of bacterial resistance mechanisms over time has impaired the action of most classes of antibiotics. Staphylococcus aureus is a notable bacterium, with high pathogenic potential and demonstrated resistance to conventional antibiotics. Considering the importance of discovering novel compounds to combat antibiotic resistance, our group previously demonstrated the antibacterial properties of limonene, a compound present in the essential oils of several plant species. OBJECTIVE: This study aimed to investigate the potential of limonene as an efflux pump (EP) inhibitor in Staphylococcus aureus strains RN-4220 and IS-58, which carry EPs for erythromycin (MrsA) and tetracycline (TetK), respectively. METHODS: The minimum inhibitory concentrations (MIC) of limonene and other efflux pump inhibitors were determined through the broth microdilution method. A reduction in the MIC of ethidium bromide was used as a parameter of EP inhibition. RESULT: While limonene was not shown to exhibit direct antibacterial effects against EP-carrying strains, in association with ethidium bromide and antibiotics, this compound demonstrated enhanced antibacterial activity, indicating the inhibition of the MrsA and TetK pumps. CONCLUSION: In conclusion, this pioneering study demonstrated the effectiveness of limonene as an EP inhibitor in S. aureus strains, RN-4220 and IS-58. Nevertheless, further studies are required to characterize the molecular mechanisms associated with limonene-mediated EP inhibition.
Assuntos
Inibidores Enzimáticos/farmacologia , Etídio/farmacologia , Limoneno/farmacologia , Staphylococcus aureus , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Produtos Biológicos/farmacologia , Interações Medicamentosas , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Staphylococcus aureus/fisiologiaRESUMO
Microdilution assays were performed in order to evaluate the antimicrobial activity of the ethanoic extract from the leaves of Bauhinia forficate (EEBF) against different microorganisms. The extract did not present inner antimicrobial activities against the tested strains. However, EEBF was able to modulate the norfloxacin-resistance against Staphylococcus aureus SA1199-B that overproduce the NorA efflux pump, once sub-inhibitory concentrations of EEBF reduced the minimal inhibitory concentratio of the norfloxacin in 87.5%. This modulatory effect was also found when the antibiotic was replaced by ethidium bromide, suggesting that EEBF acts probably by inhibition of NorA, allowing the antibiotic accumulation intracellularly, and making the line more sensitive. These results point out the EEBF potential as a source of NorA inhibitors that could be used in combination with norfloxacin for treatment of infections caused by multidrug-resistant S. aureus.
Assuntos
Bauhinia/química , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Norfloxacino/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Etídio/farmacologia , Testes de Sensibilidade Microbiana , Extratos Vegetais/farmacologia , Folhas de Planta/químicaRESUMO
INTRODUCTION: Infectious diseases have been responsible for an increasing number of deaths worldwide. Staphylococcus aureus has been recognized as one of the most notable causative agents of severe infections, while efflux pump (EP) expression is one of the main mechanisms associated with S. aureus resistance to antibiotics. OBJECTIVE: This study aimed to investigate the potential of α-pinene as an efflux pump inhibitor in species of S. aureus carrying the TetK and MrsA proteins. METHODS: The minimum inhibitory concentrations (MIC) of α-pinene and other efflux pump inhibitors were assessed using serial dilutions of each compound at an initial concentration above 1024 µg/mL. Solutions containing culture medium and bacterial inoculums were prepared in test tubes and subsequently transferred to 96-well microdilution plates. The modulation of ethidium bromide (EtBr) and antibiotics (tetracycline and erythromycin) was investigated through analysis of the modification in their MICs in the presence of a subinhibitory concentration of α-pinene (MIC/8). Wells containing only culture medium and bacterial inoculums were used as negative control. Carbonyl cyanide m-chlorophenylhydrazone (CCCP) was used as a positive control. RESULTS: The MIC of ethidium bromide against S. aureus strains RN-4220 and IS-58 was reduced by association with α-pinene. This monoterpene potentiated the effect of tetracycline against the IS-58 strain but failed in modulating the antibacterial effect of erythromycin against RN-4220, suggesting a selective inhibitory effect on the TetK EP by α- pinene. CONCLUSION: In conclusion, α-pinene has promising effects against S.aureus strains, which should be useful in the combat of antibacterial resistance associated with EP expression. Nevertheless, further research is required to fully characterize its molecular mechanism of action as an EP inhibitor.
Assuntos
Proteínas de Bactérias , Monoterpenos Bicíclicos/farmacologia , Staphylococcus aureus , Tetraciclinas , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/fisiologia , Sinergismo Farmacológico , Eritromicina/farmacologia , Etídio/farmacologia , Testes de Sensibilidade Microbiana , Monoterpenos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Tetraciclinas/farmacologiaRESUMO
Staphylococcus aureus is a Gram-positive bacterium responsible for a number of diseases and has demonstrated resistance to conventional antibiotics. This study aimed to evaluate the antibacterial activity of eugenol and its derivatives allylbenzene, 4-allylanisole, isoeugenol and 4-allyl-2,6-dimethoxyphenol against the S. aureus NorA efflux pump (EP) in association with norfloxacin and ethidium bromide. The antibacterial activity of the compounds was assessed using the broth microdilution method to determine the minimum inhibitory concentration (MIC). A reduction in the MIC of ethidium bromide (a substrate for several efflux pumps) or norfloxacin was used as a parameter of EP inhibition. Molecular modeling studies were used to predict the 3D structure and analyze the interaction of selected compounds with the binding pocket of the NorA efflux pump. Except for 4-allylanisole and allylbenzene, the compounds presented clinically effective antibacterial activity. When associated with norfloxacin against the SA 1199B strain, 4-allyl-2,6-dimethoxyphenol eugenol and isoeugenol caused significant reduction in the MIC of the antibiotic, demonstrating synergistic effects. Similar effects were observed when 4-allyl-2,6-dimethoxyphenol, allylbenzene and isoeugenol were associated with ethidium bromide. Together, these findings indicate a potential inhibition of the NorA pump by eugenol and its derivatives. This in vitro evidence was corroborated by docking results demonstrating favorable interactions between 4-allyl-2,6-dimetoxypheno and the NorA pump mediated by hydrogen bonds and hydrophobic interactions. In conclusion, eugenol derivatives have the potential to be used in antibacterial drug development in strains carrying the NorA efflux pump.
Assuntos
Proteínas de Bactérias/metabolismo , Eugenol/análogos & derivados , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Staphylococcus aureus/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Sítios de Ligação , Etídio/farmacologia , Eugenol/metabolismo , Eugenol/farmacologia , Ligação de Hidrogênio , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Norfloxacino/farmacologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
BACKGROUND: Methicillin-resistant and vancomycin-resistant Staphylococcus aureus are pathogens causing severe infectious diseases that pose real public health threats problems worldwide. In S. aureus, the most efficient multidrug-resistant system is the NorA efflux pump. For this reason, it is critical to identify efflux pump inhibitors. OBJECTIVE: In this paper, we present an update of the new natural and synthetic compounds that act as modulators of antibiotic resistance through the inhibition of the S. aureus NorA efflux pump. RESULTS: Several classes of compounds capable of restoring the antibiotic activity have been identified against resistant-S. aureus strains, acting as NorA efflux pump inhibitors. The most promising classes of compounds were quinolines, indoles, pyridines, phenols, and sulfur-containing heterocycles. However, the substantial degree structural diversity of these compounds makes it difficult to establish good structure- activity correlations that allow the design of compounds with more promising activities and properties. CONCLUSION: Despite substantial efforts put forth in the search for new antibiotic adjuvants that act as efflux pump inhibitors, and despite several promising results, there are currently no efflux pump inhibitors authorized for human or veterinary use, or in clinical trials. Unfortunately, it appears that infection control strategies have remained the same since the discovery of penicillin, and that most efforts remain focused on discovering new classes of antibiotics, rather than trying to prolong the life of available antibiotics, and simultaneously fighting mechanisms of bacterial resistance.
Assuntos
Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Infecções Estafilocócicas/tratamento farmacológico , Antibacterianos/farmacologia , Descoberta de Drogas , Farmacorresistência Bacteriana , Humanos , Indóis/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Fenóis/química , Conformação Proteica , Piridinas/química , Quinolinas/química , Relação Estrutura-Atividade , Staphylococcus aureus Resistente à Vancomicina/efeitos dos fármacosRESUMO
Bacterial resistance to antibiotics has become a public health issue around the world. The present study aimed to evaluate the antibacterial activity of chalcones isolated from flowers of Arrabidaea brachypoda, and their potential as efflux pump inhibitors of Staphylococcus aureus efflux pumps. Microdilution assays were performed with natural products from A. brachypoda. Chalcones 1, 3, 4, and 5 did not show intrinsic antimicrobial activity against all S. aureus strains tested, but they were able to potentiate the Norfloxacin action against the SA1199-B (norA) strain, with a better modulating action for the 4 trimethoxylated chalcone. All chalcones were also able to potentiate the action of EtBr against SA1199-B strain, suggesting a potential NorA inhibition. Moreover, chalcone 4 was able to interfere in the activity of MepA, and interfered weakly in the QacA/B activity. Molecular docking analyzes showed that tested chalcones are capable of binding in the hydrophobic cavity of NorA and MepA, in the same Norfloxacin binding site, indicating that chalcone 4 compete with the antibiotic for the same NorA and MepA binding sites. Association of chalcone 4 with Norfloxacin could be an alternative against multidrug resistant S. aureus over-productive of NorA or MepA.
RESUMO
This study was carried out to test the essential oil from C. ambrosioides leaves and its main constituent, α-Terpinene, in an antibacterial activity assay. As well, it was evaluated ability reduce resistance to norfloxacin and ethidium bromide was compared the Staphylococcus aureus 1199B whith 1199 wild type strain. The MIC of the C. ambrosioides essential oil and α-Terpinene were determined by microdilution method. The MIC of the essential oil and α-Terpinene presented a valueâ¯≥â¯1024⯵g/mL. However, when associated with antibacterials, the essential oil from C. ambrosioides leaves significantly reduced the MIC of antibiotics and ethidium bromide, characterizing an efflux pump inhibition. The C. ambrosioides essential oil, despite having no direct antibacterial activity against the S. aureus 1199B strain, showed a potentiating action when associated with antibacterial agents, this being attributed to an inhibition of efflux pumps.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Chenopodium ambrosioides/química , Monoterpenos/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Óleos Voláteis/farmacologia , Monoterpenos Cicloexânicos , Farmacorresistência Bacteriana/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Norfloxacino/farmacologia , Óleos Voláteis/química , Folhas de Planta/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismoRESUMO
One of the promising fields for improving the effectiveness of antimicrobial agents is their combination with efflux pump inhibitors (EPIs), which besides expanding the use of existing antibiotics. The goal of this research was to evaluate a series of aminoguanidine hydrazones (AGH's, 1-19) as antibacterial agents and NorA efflux pump inhibitors in Staphylococcus aureus strain SA-1199B. Molecular modeling and docking studies were also performed in order to explain at the molecular level the interactions of the compounds with the generated NorA efflux pump model. The MICs of the antibiotic and ethidium bromide were determined by microdilution assay in absence or presence of a subinhibitory concentration of aminoguanidine hydrazones and macrophages viability was determined through MTT assay. Bioinformatic software Swiss-Model and AutoDock 4.2 were used to perform modeling and docking studies, respectively. As results, all AGH's were able to potentiate the action for the antibiotic norfloxacin, causing MIC's reduction of 16-fold and 32-fold to ethidium bromide. In the cell viability test, the concentration of 10 µg/mL showed better results than 90% and the concentration of 1000 µg/mL showed the lowest viability, reaching a maximum of 50% for the analyzed aminoguanidine hydrazones. Molecular docking studies showed that both norfloxacin and derivative 13 were recognized by the same binding site of NorA pump, suggesting a competitive mechanism. The present work demonstrated for the first time that AGH derivatives have potential to be putative inhibitors of NorA efflux pump, showing a promising activity as an antibacterial drug development.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hidrazonas/química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Staphylococcus aureus/metabolismo , Animais , Proteínas de Bactérias/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Guanidinas/química , Hidrazonas/síntese química , Hidrazonas/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Norfloxacino/farmacologia , Estrutura Terciária de Proteína , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of organotin(IV) derivatives was investigated in vitro for their antibiotic and adjuvant antibiotic properties (efflux pump inhibitors) against Staphylococcus aureus strains that overexpress efflux pump proteins for norfloxacin (SA-1199B), erythromycin (RN-4220) and tetracycline (IS-58). Most organotin(IV) compounds showed significant antibacterial activity with small Minimum Inhibitory Concentration (MIC) values, some of which were close to 1.0µg/mL (3.1µM), but this feature was also associated with substantial cytotoxicity. Nevertheless, the cytotoxicity of these organotin(IV) compounds can be overcome when they are used as antibiotic adjuvants. Their remarkable adjuvant antibiotic properties allow potentiation of the action of tetracycline (against IS-58 strain) by up to 128-fold. This likely indicates that they can act as putative inhibitors of bacterial efflux pumps. These results reinforce organotin(IV) complexes as promising antibacterial agents, and many of these complexes, if associated with antibiotics, can act as potential adjuvant antibiotic candidates.