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1.
J Enzyme Inhib Med Chem ; 38(1): 118-137, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36305290

RESUMO

A series of novel ciprofloxacin (CP) derivatives substituted at the N-4 position with biologically active moieties were designed and synthesised. 14 compounds were 1.02- to 8.66-fold more potent than doxorubicin against T-24 cancer cells. Ten compounds were 1.2- to 7.1-fold more potent than doxorubicin against PC-3 cancer cells. The most potent compounds 6, 7a, 7b, 8a, 9a, and 10c showed significant Topo II inhibitory activity (83-90% at 100 µM concentration). Compounds 6, 8a, and 10c were 1.01- to 2.32-fold more potent than doxorubicin. Compounds 6 and 8a induced apoptosis in T-24 (16.8- and 20.1-fold, respectively compared to control). This evidence was supported by an increase in the level of apoptotic caspase-3 (5.23- and 7.6-fold, sequentially). Both compounds arrested the cell cycle in the S phase in T-24 cancer cells while in PC-3 cancer cells the two compounds arrested the cell cycle in the G1 phase. Molecular docking simulations of compounds 6 and 8a into the Topo II active site rationalised their remarkable Topo II inhibitory activity.


Assuntos
Antineoplásicos , DNA Topoisomerases Tipo II , DNA Topoisomerases Tipo II/metabolismo , Ciprofloxacina/farmacologia , Ciprofloxacina/química , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Antineoplásicos/química , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células
2.
Sci Rep ; 12(1): 18525, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36323751

RESUMO

Within healthcare settings, physicians use antibiograms, which offer information on local susceptibility rates, as an aid in selecting empirical antibiotic therapy and avoiding the prescription of potentially ineffective drugs. While antibiograms display susceptibility and resistance data at hospital, city, or region-specific levels and ultimately enable the initiation of antibiogram-based empirical antibiotic treatment, AST reports at the individual patient level and guides treatments away from broad-spectrum antibiotics towards narrower-spectrum antibiotics or the removal of antibiotics entirely. Despite these advantages, AST traditionally requires a 48- to 72-h turn-around; this window of time can be critical for some antimicrobial therapeutic interventions. Herein, we present a direct-from-specimen AST to reduce the time between patient sampling and receipt of lab AST results. The biggest challenge of performing AST directly from unprocessed clinical specimens with an unknown microbial load is aligning the categorical susceptibility report with CLSI reference methods, which start from a fixed inoculum of 0.5 McFarland units prepared using colonies from a sub-culture. In this pilot clinical feasibility study using de-identified remnant specimens collected from MCW, we observed the high and low ends of microbial loads, demonstrating a final categorical agreement of 87.5% for ampicillin, 100% for ciprofloxacin, and 100% for sulfamethoxazole-trimethoprim.


Assuntos
Antibacterianos , Ciprofloxacina , Humanos , Estudos de Viabilidade , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Ampicilina
3.
Commun Biol ; 5(1): 1234, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371541

RESUMO

Designing useful functionalities in clinically validated, old antibiotics holds promise to provide the most economical solution for the global lack of effective antibiotics, as undoubtedly a serious health threat. Here we show that using the surface chemistry of the cyclodextrin (ßCD) cycle and arginine (arg) as a linker, provides more stable ternary antibiotic complex (ßCD-arg-cpx). In contrast to classical less stable inclusion complexes, which only modify antibiotic solubility, here-presented ternary complex is more stable and controls drug release. The components of the complex intensify interactions with bacterial membranes and increase the drug's availability inside bacterial cells, thereby improving its antimicrobial efficacy and safety profile. Multifunctional antibiotics, formulated as drug delivery systems per se, that take the drug to the site of action, maximize its efficacy, and provide optical detectability are envisaged as the future in fighting against infections. Their role as a tool against multiresistant strains remains as interesting challenge open for further research.


Assuntos
Ciclodextrinas , beta-Ciclodextrinas , Ciclodextrinas/farmacologia , Ciclodextrinas/química , Arginina/química , beta-Ciclodextrinas/química , Ciprofloxacina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química
4.
Molecules ; 27(21)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36364007

RESUMO

Resin composites have been widely used in dental restoration. However, polymerization shrinkage and resultant bacterial microleakage are major limitations that may lead to secondary caries. To overcome this, a new type of antibacterial resin composite containing ciprofloxacin-loaded silver nanoparticles (CIP-AgNPs) were synthesized. The chemical reduction approach successfully produced CIP-AgNPs, as demonstrated by FTIR, zeta potential, scanning electron microscopy, and ultraviolet-visible (UV-vis) spectroscopy. CIP-AgNPs were added to resin composites and the antibacterial activity of the dental composite discs were realized against Enterococcus faecalis, Streptococcus mutans, and the Saliva microcosm. The biocompatibility of modified resin composites was assessed and mechanical testing of modified dental composites was also performed. The results indicated that the antibacterial activity and compressive strength of resin composites containing CIP-AgNPs were enhanced compared to the control group. They were also biocompatible when compared to resin composites containing AgNPs. In short, these results established strong ground application for CIP-AgNP-modified dental composite resins.


Assuntos
Nanopartículas Metálicas , Nanopartículas , Prata/farmacologia , Prata/química , Ciprofloxacina/farmacologia , Streptococcus mutans , Antibacterianos/farmacologia , Antibacterianos/química , Resinas Compostas/farmacologia , Resinas Compostas/química , Teste de Materiais , Nanopartículas/química
5.
Environ Microbiol ; 24(10): 4818-4833, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36254863

RESUMO

Overexpression of Staphylococcus aureus efflux pumps is commonly associated with antibiotic resistance, causing conventional antibiotics to be unsuccessful in combating multidrug-resistant bacterial infections. Reducing the activity of the efflux pump is an urgently required to tackle this problem. Here, we found that plantaricin A (PlnA), an antimicrobial peptide derived from Lactobacillus plantarum, had a synergistic effect with ciprofloxacin (CIP), reducing the IC90 of CIP by eight times. Subsequently, changes in membrane permeability, membrane potential, and reactive oxygen species (ROS) were determined; changes that did not explain the synergistic effect were previously observed. Ethidium bromide intake and efflux experiments showed that PlnA inhibited the function of the efflux pump by binding it and altering the structure of MepA, NorA, and LmrS. Then, a series of PlnA mutants were designed to explore the underlying mechanism; they showed that the charge and foaming of PlnA were the predominant factors affecting the structure of NorA. In a skin wound infection model, PlnA significantly reduced the dose of CIP, relieved inflammation, and promoted wound healing, indicating that PlnA and CIP synergy persisted in vivo. Overall, PlnA reduced the use of CIP for combination therapy, and allowing the continued used of CIP to kill MDR S. aureus. Multidrug-resistant Staphylococcus aureus threatens our life as a tenacious pathogen, which causes infections in hospitals, communities and animal husbandry. Various studies have showed that efflux pump inhibitors (EPIs) have been considered potential therapeutic agents for rejuvenating the activity of antibiotics. Unfortunately, small molecule EPIs exhibit several side effects that limit their use for clinical application. The present study showed a new EPI (plantaricin A) produced by Lactobacillus plantarum, which has low cytotoxicity and haemolysis and powerful inhibitory activity on efflux pumps. Therefore, it helps the design of new EPIs and controls the infection of MDR S. aureus.


Assuntos
Ciprofloxacina , Staphylococcus aureus Resistente à Meticilina , Antibacterianos/farmacologia , Proteínas de Bactérias/química , Bacteriocinas , Ciprofloxacina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo , Farmacorresistência Bacteriana Múltipla
6.
Artigo em Inglês | MEDLINE | ID: mdl-36232102

RESUMO

The gut forms a vital niche for the survival and replication of drug-resistant E. coli; however, the role of gut conditions on drug-resistant and sensitive E. coli is not clearly understood. The study aims to understand the effect of in vitro gut conditions on the spread of antibiotic resistance among E. coli and their ability to adapt to gut conditions. In this study, a multidrug-resistant (J51) and a sensitive (J254) E. coli isolate were exposed to a series of in vitro gut conditions and their growth pattern, virulence gene expression and invasion ability were studied. Further, the effect of antibiotic under in vitro gut conditions was also studied. Bile significantly affected the growth of the isolates, and the addition of iron chelator extended the lag phase of the sensitive isolate. Each in vitro gut condition had a differential effect on the expression of virulence genes in both the isolates. Further, the resistant isolate could adhere to and invade Caco2 cell lines better than the sensitive isolate. Most of the downregulated genes showed increased expression upon ciprofloxacin shock under in vitro gut conditions. The transcriptomics study revealed that exposure to bile, led to the downregulation of genes involved in different metabolic pathways. Further downregulation of metabolic pathways on ciprofloxacin shock was also observed. The downregulation of metabolic pathways could be a part of the global response played by the bacteria to adapt to harsh conditions. Reverting these fluctuated pathways could prove to be a novel strategy in combating AMR threat. Overall, bile, in high and low temperature conditions, showed a significant effect on modulating virulence gene expression on the antibiotic challenge. Thus, it is essential to consider the impact of gut conditions on gut pathogens, such as E. coli, before prescribing antimicrobial therapy during infection.


Assuntos
Anti-Infecciosos , Infecções por Escherichia coli , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Células CACO-2 , Ciprofloxacina/farmacologia , Escherichia coli , Infecções por Escherichia coli/microbiologia , Humanos , Quelantes de Ferro/farmacologia , Virulência/genética
7.
Curr Microbiol ; 79(12): 371, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36269452

RESUMO

The novel phage ST-3, capable of infecting the foodborne pathogen Salmonella Typhimurium, was isolated from wastewater. The Biological characters and genome information of ST-3 were analyzed. In the in vitro assay, the phage ST-3 with a MOI of 10 effectively inhibited the growth of Salmonella Typhimurium CGMCC 1.1174 in 6 h. The inhibitory effect of combination phage ST-3 and antibiotics was also studied, the removal rate of planktonic host exposed to ST-3 and levofloxacin hydrochloride at the same time, or to ciprofloxacin followed by ST-3, is higher than that exposed to antibiotic dosing group alone and antibiotic + phage dosing group. The phage ST-3 combined with 0.5 µg/mL levofloxacin hydrochloride resulted in the largest decrease in biofilm biomass at 54%. The phage ST-3 could be a potential agent to control Salmonella Typhimurium growth and provide instruction for use it and antibiotics together.


Assuntos
Bacteriófagos , Fagos de Salmonella , Salmonella typhimurium/genética , Antibacterianos/farmacologia , Levofloxacino/farmacologia , Águas Residuárias , Ciprofloxacina/farmacologia , Bacteriófagos/genética , Myoviridae , Fagos de Salmonella/genética
8.
Nat Commun ; 13(1): 6279, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36270992

RESUMO

Diabetic wound is one of the most intractable chronic wounds that is prone to bacterial infection. Hypoxia is an important feature in its microenvironment. However, it is challenging for antimicrobial therapy to directly apply the existing hypoxia-responsive drug delivery systems due to the active targeting deficiency and the biofilm obstacle. Herein, we customizes a hypoxia-responsive carrier, lactose-modified azocalix[4]arene (LacAC4A) with the ability to actively target and inhibit biofilm. By loading ciprofloxacin (Cip), the resultant supramolecular nanoformulation Cip@LacAC4A demonstrates enhanced antibacterial efficacy resulting from both the increased drug accumulation and the controlled release at the site of infection. When applied on diabetic wounds together with multidrug-resistant Pseudomonas aeruginosa infection in vivo, Cip@LacAC4A induces definitely less inflammatory infiltration than free Cip, which translates into high wound healing performance. Importantly, such design principle provides a direction for developing antimicrobial drug delivery systems.


Assuntos
Anti-Infecciosos , Diabetes Mellitus , Infecções por Pseudomonas , Humanos , Pseudomonas aeruginosa , Lactose , Testes de Sensibilidade Microbiana , Preparações de Ação Retardada , Úlcera/tratamento farmacológico , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Biofilmes , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Sistemas de Liberação de Medicamentos , Hipóxia/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Diabetes Mellitus/tratamento farmacológico
9.
J Vet Med Sci ; 84(11): 1502-1507, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36198611

RESUMO

Campylobacter and non-typhoidal Salmonella are the major causes of bacterial gastrointestinal infections in humans. Although antimicrobial therapy is typically not recommended in many cases of these infections, it may be life-saving in patients with severe symptoms. Since chicken eggs and meat derived from layers are destined for human consumption, we investigated the prevalence and antimicrobial resistance of these two bacterial genera in 82 layer flocks at chicken processing plants in Honshu, Japan. Campylobacter was isolated from 77 flocks (93.9%). Resistance to ampicillin, tetracycline, and ciprofloxacin was documented in 42.3 (30/71), 16.9 (12/71), and 14.1% (10/71) of Campylobacter jejuni, respectively. Multilocus-sequence typing identified ST4389 and ST5262 as the most frequent C. jejuni sequence types. In C. coli, resistance to ampicillin, tetracycline, and ciprofloxacin was found in 20.0 (7/35), 20.0 (7/35), and 25.7% (9/35), respectively. The most frequent sequence type in C. coli was ST8292. Erythromycin resistance was not observed among Campylobacter species. Salmonella was isolated from 14 flocks (17.1%). The two most frequent serovars were Salmonella Corvallis and S. Braenderup. Neither S. Enteritidis nor S. Infantis were isolated. Streptomycin resistance was observed in six isolates (26.1%), and all isolates were susceptible to cefotaxime and ciprofloxacin. Thus, chicken eggs and meat derived from layers are possible sources of these bacterial infections in humans. The antimicrobial susceptibility of these isolates was maintained, reflecting restrictions on the use of antimicrobial agents on layers.


Assuntos
Infecções por Campylobacter , Campylobacter jejuni , Campylobacter , Humanos , Animais , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Prevalência , Japão/epidemiologia , Testes de Sensibilidade Microbiana/veterinária , Campylobacter jejuni/genética , Salmonella , Infecções por Campylobacter/epidemiologia , Infecções por Campylobacter/veterinária , Infecções por Campylobacter/microbiologia , Ciprofloxacina/farmacologia , Tetraciclina/farmacologia , Galinhas/microbiologia , Ampicilina
10.
Diagn Microbiol Infect Dis ; 104(4): 115798, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36215941

RESUMO

The detection of resistance without the need for culture is essential to establish a guided treatment against Neisseria gonorrhoeae (NG) infections. We evaluated the VIASURE Neisseria gonorrhoeae ciprofloxacin resistant Real Time PCR Detection Kit (CerTest Biotec S.L, Zaragoza, Spain) for the simultaneous identification and direct detection of ciprofloxacin susceptibility in 88 NG isolates and 133 positive NG clinical samples of different anatomical location. The sensitivity for NG detection was 93.2% and the specificity 100%. The sensitivity of the test to characterize resistance/susceptibility to ciprofloxacin was (96.5%). In conclusion, the test evaluated is suitable for use to establish a targeted therapy with oral ciprofloxacin in case of not detecting resistance.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Humanos , Neisseria gonorrhoeae/genética , Ciprofloxacina/farmacologia , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Gonorreia/diagnóstico , Gonorreia/tratamento farmacológico , Farmacorresistência Bacteriana
11.
Microb Genom ; 8(10)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36301086

RESUMO

Salmonella is a leading cause of foodborne outbreaks and systemic infections worldwide. Emerging multi-drug resistant Salmonella lineages such as a ciprofloxacin-resistant subclade (CIPR) within Salmonella enterica serovar Kentucky ST198 threaten the effective prevention and treatment of infections. To understand the genomic diversity and antimicrobial resistance gene content associated with S. Kentucky in Switzerland, we whole-genome sequenced 70 human clinical isolates obtained between 2010 and 2020. Most isolates belonged to ST198-CIPR. High- and low-level ciprofloxacin resistance among CIPR isolates was associated with variable mutations in ramR and acrB in combination with stable mutations in quinolone-resistance determining regions (QRDRs). Analysis of isolates from patients with prolonged ST198 colonization indicated subclonal adaptions with the ramR locus as a mutational hotspot. SNP analyses identified multiple clusters of near-identical isolates, which were often associated with travel but included spatiotemporally linked isolates from Switzerland. The largest SNP cluster was associated with travellers returning from Indonesia, and investigation of global data linked >60 additional ST198 salmonellosis isolates to this cluster. Our results emphasize the urgent need for implementing whole-genome sequencing as a routine tool for Salmonella surveillance and outbreak detection.


Assuntos
Anti-Infecciosos , Salmonella enterica , Humanos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Testes de Sensibilidade Microbiana , Suíça/epidemiologia , Metagenômica , Farmacorresistência Bacteriana/genética , Ciprofloxacina/farmacologia , Genômica , Anti-Infecciosos/farmacologia
12.
BMC Microbiol ; 22(1): 250, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36253712

RESUMO

BACKGROUND: Infection of Salmonella enterica subsp. enterica serovar Typhi is the primary etiology of typhoid fever globally and is common in many developing countries, especially those with dense populations and poor environmental sanitation. Antibiotic fluoroquinolones were used for the treatment in the 1980s due to the resistance to the first-line antibiotics. However, many cases of treatment failure of fluoroquinolones in typhoidal patients have been reported from numerous countries in Asia, Europe, Africa, and America. Mutations in quinolone resistance determining regions (QRDR) genes, gyrA, gyrB, parC, and parE, are found in fluoroquinolone-resistant Salmonella Typhi. Contrast reports came from the S. Typhi isolates in Indonesia, mainly Jakarta and the surroundings, obtained from patients with typhoid fever, with good sensitivity to the fluoroquinolones, i.e., nalidixic acid, ciprofloxacin, moxifloxacin, and levofloxacin. The present study, therefore, aimed to identify the hotspot sequences of gyrA, gyrB, parC, and parE genes of the local S. Typhi strains based on their susceptibility to fluoroquinolones from patients with typhoid fever in Jakarta and its satellite cities. RESULTS: A total of 28 isolates were identified as S. Typhi. All isolates were susceptible to nalidixic acid, levofloxacin, and moxifloxacin. Twenty-seven isolates (96.4%) were susceptible to ciprofloxacin, with one isolate (3.6%) being intermediate. The hotspot sequences of gyrA, gyrB, parC, and parE genes from all isolates were identical to the fluoroquinolone-sensitive reference sequence Salmonella enterica subsp. enterica serovar Typhi Ty2 (NCBI GenBank AE014613.1), including the isolate with intermediate susceptibility. The mutation was not found, and amino acid deduced from all hotspots in susceptible and intermediate isolates showed no replacement in all reported codons. CONCLUSIONS: This study showed that the local S. Typhi strains from Jakarta and surroundings were susceptible to fluoroquinolones (nalidixic acid, ciprofloxacin, levofloxacin, and moxifloxacin), and the hotspot sequences of the gyrA, gyrB, parC, and parE genes were all identical to the reference sequence. Thus, the hotspot sequences of the gyrA, gyrB, parC, and parE genes seemingly were conserved in Jakarta's local S. Typhi strains and could be considered wild type. The phenotypic susceptibility was consistent with the genotypic characteristic without non-synonymous mutations associated with drug resistance.


Assuntos
Quinolonas , Salmonella enterica , Febre Tifoide , Aminoácidos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ciprofloxacina/farmacologia , DNA Girase/genética , DNA Topoisomerase IV/genética , Farmacorresistência Bacteriana/genética , Fluoroquinolonas/farmacologia , Humanos , Levofloxacino , Testes de Sensibilidade Microbiana , Moxifloxacina , Ácido Nalidíxico , Salmonella , Salmonella typhi
13.
J Med Chem ; 65(20): 14049-14065, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36219830

RESUMO

A library of eight new fluoroquinolone-nuclease conjugates containing a guanidinoethyl or aminoethyl auxiliary pendant on the cyclen moiety was designed and synthesized to investigate their potential for overcoming the general issue of "metallodrug vulnerability" under physiological conditions. The Cu(II) and Co(III) complexes of the new designer compounds were synthesized, and their potential to operate a dynamic, intramolecular cap with DNase activity was explored. The lead Co(III)-cyclen-ciprofloxacin conjugate showed excellent in vitro hydrolytic DNase activity, which was retained in the presence of strong endogenous chelators and exhibited enhanced antibacterial activity relative to the metal-free ligand (in the absence of any adjuvants), thereby demonstrating a "proof of concept" in vitro and ex vivo, respectively, for the dynamic cap hypothesis. The lead conjugate nicked supercoiled plasmid DNA within the fluoroquinolone-gyrase-DNA ternary complex and thereby disabled the function of gyrase, a new mode of action not previously reported for any fluoroquinolone.


Assuntos
Ciclamos , Fluoroquinolonas , Fluoroquinolonas/farmacologia , Ligantes , Ciprofloxacina/farmacologia , Antibacterianos/farmacologia , Quelantes , Desoxirribonucleases
14.
Microbiologyopen ; 11(5): e1316, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36314749

RESUMO

Antibiotic resistance is becoming increasingly prevalent amongst bacterial pathogens and there is an urgent need to develop new types of antibiotics with novel modes of action. One promising strategy is to develop resistance-breaker compounds, which inhibit resistance mechanisms and thus resensitize bacteria to existing antibiotics. In the current study, we identify bacterial DNA double-strand break repair as a promising target for the development of resistance-breaking co-therapies. We examined genetic variants of Escherichia coli that combined antibiotic-resistance determinants with DNA repair defects. We observed that defects in the double-strand break repair pathway led to significant resensitization toward five bactericidal antibiotics representing different functional classes. Effects ranged from partial to full resensitization. For ciprofloxacin and nitrofurantoin, sensitization manifested as a reduction in the minimum inhibitory concentration. For kanamycin and trimethoprim, sensitivity manifested through increased rates of killing at high antibiotic concentrations. For ampicillin, repair defects dramatically reduced antibiotic tolerance. Ciprofloxacin, nitrofurantoin, and trimethoprim induce the promutagenic SOS response. Disruption of double-strand break repair strongly dampened the induction of SOS by these antibiotics. Our findings suggest that if break-repair inhibitors can be developed they could resensitize antibiotic-resistant bacteria to multiple classes of existing antibiotics and may suppress the development of de novo antibiotic-resistance mutations.


Assuntos
Infecções por Escherichia coli , Proteínas de Escherichia coli , Humanos , Escherichia coli/metabolismo , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Nitrofurantoína/metabolismo , Nitrofurantoína/farmacologia , Reparo do DNA , Ciprofloxacina/farmacologia , Testes de Sensibilidade Microbiana , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Trimetoprima/metabolismo , Trimetoprima/farmacologia
15.
Environ Pollut ; 315: 120440, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36265724

RESUMO

Antibiotics play an essential role in the medical healthcare world, but their widespread usage and high prevalence have posed negative environmental consequences. During the past few decades, various antibiotic drugs have been detected in aquatic and terrestrial ecosystems. Among them, the Fluoroquinolones (FQ) group is ubiquitous in the environment and has emerged as a major environmental pollutant. FQs are very significant, broad-spectrum antibiotics used in treating various pathogenic diseases of humans and animals. The most known and used FQs are ciprofloxacin, norfloxacin, ofloxacin, levofloxacin, enrofloxacin, danofloxacin, and moxifloxacin. After human and animal administration, about 70% of these drugs are excreted out in unaltered form into the environment. Besides, wastewater discharge from pharmaceutical industries, hospitals, and agriculture runoff is the major contributor to the accumulation of FQs into the ecosystem. Their long-term presence in the environment creates selection pressure on microorganisms and contributes to the emergence of multi-drug-resistant bacteria. In addition to the resistance, these antibiotics also impose ecotoxicological effects on various animals and plant species. The presence of the fluorine atom in Fluoroquinolones makes them highly electronegative, strong, recalcitrant, and less compatible with microbial degradation. Many biological and chemical processes have been invented and successfully implemented during the past few decades for the elimination of these pollutants from the environment. This review provides a detailed overview of the classification, occurrence, distribution, and ecotoxicological effects of Fluoroquinolones. Their modes of action, resistance mechanism, detection and analysis methods, and remediation strategies have also been discussed in detail.


Assuntos
Ecossistema , Fluoroquinolonas , Animais , Humanos , Fluoroquinolonas/análise , Ciprofloxacina/farmacologia , Antibacterianos/química , Levofloxacino
16.
BMJ Open Ophthalmol ; 7(Suppl 1): A6, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-36161816

RESUMO

*Correspondence - Stephen Kaye: S.B.Kaye@liverpool.ac.uk INTRODUCTION: Pseudomonas aeruginosa injects toxins, ExoS or ExoU, into host cells via the type III secretion system (T3SS) which destroy cells and help evade the immune system. First-line fluoroquinolones demonstrate better in vitro activity against P. aeruginosa but in certain clinical situations aminoglycosides are more effective. We evaluate the effects of fluoroquinolones (moxifloxacin and ciprofloxacin) and aminoglycosides (tobramycin and gentamycin) on T3SS and toxin expression, and the associated toxicity in corneal epithelial cell infection models. METHODS: Expression levels of pcrV (T3SS needle component) from ExoU-expressing PA103 and ExoS-expressing PA76026 after 16h incubation in each antimicrobial was detected using western blotting. qRT PCR detected mRNA levels of ExoU, ExoS, pcrV and ExsA (T3SS activating factor) after PA103 and PA76026 were exposed to tobramycin and moxifloxacin. LIVE/DEAD and LDH assays after 24h evaluated how the antimicrobials influenced acute cytotoxicity in a HCE-T cell scratch and infection model. RESULTS: Tobramycin significantly reduced pcrV in both strains by 50.5-74.0% compared to the fluoroquinolones (p=0.001 and 0.003), even at low concentrations. Fluoroquinolones significantly increased pcrV by 57.0-81.8% (p=0.004 and 0.003). mRNA levels of ExoU, ExoS, pcrV and ExsA were reduced by tobramycin but moxifloxacin increased pcrV, ExsA and ExoS. Tobramycin, despite more bacterial expansion compared to the same relative concentrations of fluoroquinolones, reduced ExoU/ExoS cytotoxicity and allowed complete wound healing. DISCUSSION: Tobramycin downregulates T3SS expression and reduces ExoS/ExoU mediated cytotoxicity which protects infected HCE-T cells even at low concentrations. Fluoroquinolones however upregulated T3SS and do not negate the cytotoxic effects.


Assuntos
Toxinas Bacterianas , Infecções por Pseudomonas , ADP Ribose Transferases/genética , Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Toxinas Bacterianas/genética , Ciprofloxacina/farmacologia , Dieldrin/análogos & derivados , Fluoroquinolonas/farmacologia , Gentamicinas/metabolismo , Humanos , Moxifloxacina/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/genética , RNA Mensageiro/metabolismo , Tobramicina/farmacologia , Sistemas de Secreção Tipo III/genética , Fatores de Virulência/genética
17.
Microb Pathog ; 171: 105745, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36057414

RESUMO

This study aimed to investigate the presence of eight virulence genes (ace, asa1, esp, efaA, gelE, cylA, agg, fsr) in Enterococcus from a variety of animals and to explore the drug resistance and pathogenicity. This could provide a theoretical basis for clinical treatment of Enterococcus infections. Anal swabs from pigs, chickens, cattle, and dogs in farms and pet hospitals were collected for Enterococcus isolation and identification. Eight virulence genes were detected (PCR method), and drug resistance was assessed (drug-sensitive paper method). The strains containing different virulence genes were then divided into EV1, EV2, and EV3 groups. The LD50 and pathogenicity was examined by intra-peritoneal injection to infect mice. Differences were found in the detection rates of virulence genes in Enterococcus from the different animals. The highest overall detection rate was for the esp gene (78.0%), and the lowest for the cylA gene (15.5%). Eight genes were detected most frequently in Enterococcus from dogs and least frequently from cattle. Among the Enterococcus strains from four variety of animals, drug resistance was highest against sulfamethoxazole (100%), cefotaxime (>97%), and cefotaxitin (>93%). Drug resistance was lowest against vancomycin (0%), levofloxacin (<12%) and ciprofloxacin (<13%). The LD50 for each of the three groups was EV1LD50=8.71×109CFU, EV2LD50=2.34×1010CFU,and EV3LD50=9.33×1010CFU. The Enterococcus12LD50 dose group caused significant clinical symptoms in mice, with pathological effects on the heart, liver, lungs, and kidneys, and particularly on the urinary system. The abundance of Enterococcus virulence genes, drug resistance, and pathogenicity vary among different animal origins, and the pathology caused by Enterococcus requires effective treatment protocols based on species and regional characteristics.


Assuntos
Enterococcus faecium , Infecções por Bactérias Gram-Positivas , Animais , Animais Domésticos , Antibacterianos/farmacologia , Bovinos , Cefotaxima/farmacologia , Galinhas , Ciprofloxacina/farmacologia , Cães , Resistência a Medicamentos , Farmacorresistência Bacteriana/genética , Enterococcus , Enterococcus faecalis , Infecções por Bactérias Gram-Positivas/veterinária , Levofloxacino/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Sulfametoxazol/farmacologia , Suínos , Vancomicina/farmacologia , Virulência/genética , Fatores de Virulência/genética
18.
Microb Drug Resist ; 28(10): 972-979, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36108336

RESUMO

Antibiotic combinations remain the frontline therapy for severe infections to reduce mortality. However, conventional antibiotic combinations have some limitations such as the low bioavailability and the rise of resistant strains. Nanoparticles are increasingly used as antibiotic delivery systems to promote bioavailability and hence improve efficacy of antibiotics. In this work, we hypothesize that the simultaneous delivery of two antibiotic-loaded nanoparticles will improve the intracellular bioavailability and thus inhibit emergence of resistance. Accordingly, Chitosan-pluronic nanoparticles were used to construct nanosized ciprofloxacin and meropenem and the antibacterial activity of nanosized combined antibiotics were compared versus unloaded single, unloaded combined, and nanosized single antibiotics. Thirty-six stepwise mutants were selected by exposing two E. coli strains to increasing concentrations of free-unloaded and nanosized antibiotics, and mutants were tested for antimicrobial susceptibilities using broth microdilution and disc diffusion methods. The change in expression levels of acrB efflux pump and porins (ompC and ompF) was assessed by real-time reverse transcription-PCR. The in vitro evaluation of combined ciprofloxacin and meropenem-loaded nanoparticles demonstrated that this nanosystem exhibited enhanced antibacterial effect. Step mutants selected with nanosized combined antibiotics showed higher sensitivity to both drugs, exhibited lower mutation frequencies, and less cross-resistance to other antimicrobial classes. Moreover, for all steps of selection, nanosized combined antibiotic mutants expressed significantly lower levels of acrB as well as higher levels of ompC and ompF (p-value <0.01). In view of these results, the use of nanosized combined antibiotics may be considered among the new promising strategies to combat infections through their potential efficacy in reducing microorganisms' ability to form resistant mutants.


Assuntos
Anti-Infecciosos , Quitosana , Infecções por Escherichia coli , Proteínas de Escherichia coli , Humanos , Escherichia coli , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Meropeném/farmacologia , Quitosana/farmacologia , Poloxâmero/metabolismo , Poloxâmero/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Porinas/metabolismo , Ciprofloxacina/farmacologia , Anti-Infecciosos/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo
19.
Ann Med ; 54(1): 2500-2510, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36120867

RESUMO

Objective: To determine the minimum inhibitory concentration (MIC) distribution of antibacterial drugs and the susceptibility of non-tuberculous mycobacterial (NTM) isolates to provide a reference basis for the clinical selection of an effective starting regimen.Methods: The common clinical isolates of NTM in the respiratory tract, which met the standards of the American Thoracic Society for NTM lung disease, were collected. The MICs of 81 isolates were determined using the microbroth dilution method (Thermo Fisher Scientific, USA), as recommended by the Clinical and Laboratory Standards Institute, USA.Results: Included were 43 Mycobacterium avium complex (MAC) strains, 24 M. abscessus complex (MAB) strains, and 14 M. kansasii strains. The sensitivity rates of MAC to clarithromycin and amikacin were 81.4% and 79.1%, respectively, while the sensitivity rates to linezolid and moxifloxacin were only 20.9% and 9.3%; the MIC of rifabutin was the lowest (MIC50% was just 2 µg/mL). After incubation for 3-5 days, the sensitivity rate of MAB to clarithromycin was 87.5%; this decreased to 50% after 14 days' incubation. Most of them were susceptible to amikacin (91.6%), and most were resistant to moxifloxacin (95.8%), ciprofloxacin (95.8%), imipenem (95.8%), amoxicillin/clavulanate (95.8%), tobramycin (79.1%), doxycycline (95.8%) and trimethoprim/sulfamethoxazole (95.8%). intermediate (83.3%) and resistant (16.7%) to cefoxitin. The susceptibility to linezolid was only 33.3%. The sensitivity and resistance breakpoints of tigecycline were set to ≤0.5 and ≥8 µg/mL, respectively, and the sensitivity and resistance rates were 50% and 0%, respectively. M. kansasii was susceptible to clarithromycin, amikacin, linezolid, moxifloxacin, rifampicin and rifabutin (100%).Discussion: In Wenzhou, clarithromycin, amikacin and rifabutin have good antibacterial activity against MAC, while linezolid and moxifloxacin have high resistance. Amikacin and tigecycline have strong antibacterial activity against MAB, while most other antibacterial drugs are resistant to varying degrees. Most antibacterial drugs are susceptible to M. kansasii and have good antibacterial activity.Conclusion: The identification of NTM species and the detection of their MICs have certain guiding values for the treatment of NTM lung disease.Key MessageThe three most common respiratory non-tuberculous mycobacterial (NTM) isolates with clinical significance in the Wenzhou area were tested for drug susceptibility. The broth microdilution method was used to determine the minimum inhibitory concentration distribution of antibacterial drugs and the susceptibility of NTM isolates to provide a reference basis for the clinical selection of an effective starting regimen.


Assuntos
Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Amicacina/farmacologia , Amicacina/uso terapêutico , Amoxicilina , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefoxitina/farmacologia , Cefoxitina/uso terapêutico , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Claritromicina/farmacologia , Ácido Clavulânico/farmacologia , Ácido Clavulânico/uso terapêutico , Doxiciclina/farmacologia , Doxiciclina/uso terapêutico , Humanos , Imipenem/farmacologia , Imipenem/uso terapêutico , Linezolida/farmacologia , Linezolida/uso terapêutico , Testes de Sensibilidade Microbiana , Moxifloxacina/farmacologia , Moxifloxacina/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas , Sistema Respiratório , Rifabutina/farmacologia , Rifabutina/uso terapêutico , Rifampina/farmacologia , Rifampina/uso terapêutico , Sulfametoxazol/farmacologia , Sulfametoxazol/uso terapêutico , Tigeciclina/farmacologia , Tigeciclina/uso terapêutico , Tobramicina/farmacologia , Tobramicina/uso terapêutico , Trimetoprima/farmacologia , Trimetoprima/uso terapêutico
20.
Biol Open ; 11(10)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36063129

RESUMO

The Gram-positive bacterium Staphylococcus aureus is responsible for a number of infections and has been described to exhibit resistance to antibacterial drugs through different resistance mechanisms. Among these, active efflux has been shown to be one of the main mechanisms of bacterial resistance associated with S. aureus. In this sense, the aim of the present study was to evaluate the ability of ellagic acid and gallic acid to reverse resistance by inhibiting the efflux pumps present in S. aureus strains IS-58 and K2068, which express the TetK and MepA flux pumps, respectively. In addition, the toxicity of both compounds was verified in Drosophila melanogaster. Broth microdilution assays were performed to obtain the minimum inhibitory concentration (MIC) values of ellagic acid and gallic acid, whereas efflux pump inhibition was tested using a subinhibitory concentration of standard efflux pump inhibitors, gallic acid and ellagic acid (MIC/8), where the ability of these compounds to decrease the MIC of ethidium bromide (EtBr) and antibiotics was verified. Toxicity was evaluated by mortality and negative geotaxis assays in D. melanogaster. Ellagic acid and gallic acid showed no direct antibacterial activity on S. aureus strains carrying the efflux pumps TetK and MepA. However, when we looked at the results for the TetK pump, we saw that when the two acids were associated with the antibiotic tetracycline, a potentiation of the antibacterial effect occurred; this behavior was also observed for the antibiotic ciprofloxacin in the MepA strain. For the efflux pump inhibition results, only the compound gallic acid showed potentiating effect on antibacterial activity when associated with the substrate EtBr for the IS-58 strain carrying the TetK efflux pump. Ellagic acid and gallic acid showed no toxicity on the model arthropod D. melanogaster. These results indicate the possible use of gallic acid as an adjuvant in antibiotic therapy against multidrug-resistant bacteria.


Assuntos
Ácido Elágico , Staphylococcus aureus , Animais , Antibacterianos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/farmacologia , Ciprofloxacina/farmacologia , Drosophila melanogaster , Ácido Elágico/farmacologia , Etídio/farmacologia , Ácido Gálico/farmacologia , Tetraciclina/farmacologia
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