Preparation, Physicochemical Characterization, Antimicrobial Effects, Biocompatibility and Cytotoxicity of Co-Loaded Meropenem and Vancomycin in Mesoporous Silica Nanoparticles.

Mesoporous silica nanoparticles (MSNPs) have been reported as an effective system to co-deliver a variety of different agents to enhance efficiency and improve biocompatibility. This study was aimed at the preparation, physicochemical characterization, antimicrobial effects, biocompatibility, and cytotoxicity of vancomycin and meropenem co-loaded in the mesoporous silica nanoparticles (Van/Mrp-MSNPs). The prepared nanoparticles were explored for their physicochemical features, antibacterial and antibiofilm effects, biocompatibility, and cytotoxicity. The minimum inhibitory concentrations (MICs) of the Van/Mrp-MSNPs (0.12-1 µg/mL) against Staphylococcus aureus isolates were observed to be lower than those of the same concentrations of vancomycin and meropenem. The minimum biofilm inhibitory concentration (MBIC) range of the Van/Mrp-MSNPs was 8-64 µg/mL, which was lower than the meropenem and vancomycin MBICs. The bacterial adherence was not significantly decreased upon exposure to levels lower than the MICs of the MSNPs and Van/Mrp-MSNPs. The viability of NIH/3T3 cells treated with serial concentrations of the MSNPs and Van/Mrp-MSNPs were 73-88% and 74-90%, respectively. The Van/Mrp-MSNPs displayed considerable inhibitory effects against MRSA, favorable biocompatibility, and low cytotoxicity. The Van/Mrp-MSNPs could be a potential system for the treatment of infections.

Collateral sensitivity: An evolutionary trade-off between antibiotic resistance mechanisms, attractive for dealing with drug-resistance crisis.

Background: The discovery and development of antimicrobial drugs were one of the most significant advances in medicine, but the evolution of microbial resistance limited the efficiency of these drugs. Aim: This paper reviews the collateral sensitivity in bacteria and its potential and limitation as a new target for treating infections. Results and Discussion: Knowledge mechanisms of resistance to antimicrobial agents are useful to trace a practical approach to treat and control of resistant pathogens. The effect of a resistance mechanism to certain antibiotics on the susceptibility or resistance to other drugs is a key point that may be helpful for applying a strategy to control resistance challenges. In an evolutionary trade-off known as collateral sensitivity, the resistance mechanism to a certain drug may be mediated by the hypersensitivity to other drugs. Collateral sensitivity has been described for different drugs in various bacteria, but the molecular mechanisms affecting susceptibility are not well demonstrated. Collateral sensitivity could be studied to detect its potential in the battle against resistance crisis as well as in the treatment of pathogens adapting to antibiotics. Collateral sensitivity-based antimicrobial therapy may have the potential to limit the emergence of antibiotic resistance.

In-vitro Effect of Imipenem, Fosfomycin, Colistin, and Gentamicin Combination against Carbapenem-resistant and Biofilm-forming Pseudomonas aeruginosa Isolated from Burn Patients.

The aim of this study was to investigate in-vitro antibacterial and antibiofilm effect of colistin, imipenem, gentamicin, and fosfomycin alone and the various combinations against carbapenem-resistant Pseudomonas aeruginosa (P. aeruginosa). Eight carbapenem-resistant and biofilm-forming P. aeruginosa isolates from burn patients were collected. The mechanisms of resistance to carbapenem were determined by the phenotypic, PCR, and Real-Time PCR assays. The minimum inhibitory concentration (MIC) of antimicrobial agents was determined by the broth micro dilution. To detect any inhibitory effect of antibiotics against the biofilm, the biofilm inhibitory concentration was determined. To detect synergetic effects of the combinations of antibiotics, the checkerboard assay and the fractional inhibitory concentration (FIC) were used. The highest synergic effect was observed in colistin/fosfomycin and gentamicin/fosfomycin (5 of 8 isolates), and the lowest synergic effect was found in gentamicin/imipenem and colistin/gentamicin (1 of 8 isolates). Colistin/fosfomycin, imipenem/fosfomycin, colistin/imipenem, gentamicin/fosfomycin, and gentamicin/imipenem were shown synergic effect for 3, 2, 2, 2 and 1 isolates, respectively. The combination of antibiotics had different effects on biofilm and planktonic forms of P. aeruginosa. Therefore, a separate determination of inhibitory effects of the antibiotic in the combination is necessary. Fosfomycin/colistin and fosfomycin/gentamicin were more effective against planktonic form and fosfomycin/colistin against biofilm forms.

Tightly controlled response to oxidative stress; an important factor in the tolerance of Bacteroides fragilis.

The exposure of Bacteroides fragilis to highly oxygenated tissues induces an oxidative stress due to a shift from the reduced condition of the gastrointestinal tract to an aerobic environment of host tissues. The potent and effective responses to reactive oxygen species (ROS) make the B. fragilis tolerant to atmospheric oxygen for several days. The response to oxidative stress in B. fragilis is a complicated event that is induced and regulated by different agents. In this review, we will focus on the B. fragilis response to oxidative stress and present an overview of the regulators of responses to oxidative stress in this bacterium.

Molecular mechanisms associated with quinolone resistance in Enterobacteriaceae: review and update.

BACKGROUND: Quinolones are broad-spectrum antibiotics, which are used for the treatment of different infectious diseases associated with Enterobacteriaceae. During recent decades, the wide use as well as overuse of quinolones against diverse infections has led to the emergence of quinolone-resistant bacterial strains. Herein, we present the development of quinolone antibiotics, their function and also the different quinolone resistance mechanisms in Enterobacteriaceae by reviewing recent literature. METHODS: All data were extracted from Google Scholar search engine and PubMed site, using keywords; quinolone resistance, Enterobacteriaceae, plasmid-mediated quinolone resistance, etc. RESULTS AND CONCLUSION: The acquisition of resistance to quinolones is a complex and multifactorial process. The main resistance mechanisms consist of one or a combination of target-site gene mutations altering the drug-binding affinity of target enzymes. Other mechanisms of quinolone resistance are overexpression of AcrAB-tolC multidrug-resistant efflux pumps and downexpression of porins as well as plasmid-encoded resistance proteins including Qnr protection proteins, aminoglycoside acetyltransferase (AAC(6')-Ib-cr) and plasmid-encoded active efflux pumps such as OqxAB and QepA. The elucidation of resistance mechanisms will help researchers to explore new drugs against the resistant strains.

Epigenetic modifications in gastric cancer: Focus on DNA methylation.

Gastric cancer is a complex heterogeneous disease which is the fourth prevalent malignancy worldwide. Although, several diagnosis and treatment are available for the gastric cancer patients, however the malignancy is still the third leading cause of cancer-related death in the world. Beside the genetic and environmental factors, epigenetic alterations are also involved in the emergence of gastric cancer. Epigenetics alterations are heritable changes which regulate gene expression without occurring changes in DNA sequence. Epigenetic changes mostly include DNA methylation, histon post-translational modifications, chromatin remodeling and non-coding RNAs. Among the mentioned epigenetic modifications, DNA methylation is a major epigenetic process that plays a key role in different stages of evolution and cancer development. In this review, we address all types of related epigenetic modifications in gastric cancer by focus on DNA methylation by reviewing the recent literatures. Understanding of molecular mechanisms of epigenetics alterations in gastric cancer development helps researchers to identify new epigenetic drugs against the malignancy.

Frequency of DNA gyrase and topoisomerase IV mutations and plasmid-mediated quinolone resistance genes among Escherichia coli and Klebsiella pneumoniae isolated from urinary tract infections in Azerbaijan, Iran.

OBJECTIVES: This study assessed genetic alterations in gyrA, gyrB, parC and parE and the prevalence of plasmid-mediated quinolone resistance (PMQR) genes among Escherichia coli and Klebsiella pneumoniae isolates from urinary tract infections (UTIs) in Azerbaijan, Iran. METHODS: A total of 205 clinical isolates of E. coli (n=177) and K. pneumoniae (n=28) were obtained from UTIs. Antimicrobial susceptibility was determined by disk diffusion and agar dilution assays. The presence of PMQR genes was determined by PCR, and sequencing of the gyrA, gyrB, parC and parE was performed. RESULTS: The rate of fluoroquinolone (FQ) resistance among the isolates was 77.1%. The Ser83Leu mutation in gyrA was observed in all 60 FQ-resistant isolates selected for direct sequencing. The second most common mutation in gyrA was Asp87Asn. Frequent mutations in parC were Ser80Ile and Glu84Val. Ser359Ala+Ser367Thr and Gly385Cys mutations in gyrB were identified in one isolate each of K. pneumoniae and E. coli, respectively. The parE gene had mutations at Ile529Leu, Ser458Ala and Leu416Phe. Overall, PMQR determinants were identified in 90% of E. coli and 100% of K. pneumoniae. The prevalence of PMQR genes was as follows: aac(6')-Ib-cr, 71.7%; oqxB, 51.7%; oqxA, 36.7%; qnrB, 28.3%; qnrS, 21.7%; qnrD, 16.7%; qepA, 5.0%; qnrA, 1.7%; and qnrC, 1.7%. CONCLUSIONS: FQ resistance rates were high. Mutations in DNA gyrase and topoisomerase IV and the prevalence of PMQR genes in E. coli and K. pneumoniae isolates were alarming. Moreover, the combination of these resistance mechanisms plays an important role in high-level FQ resistance.

The rates of quinolone, trimethoprim/sulfamethoxazole and aminoglycoside resistance among Enterobacteriaceae isolated from urinary tract infections in Azerbaijan, Iran.

Aim: Antibiotic susceptibility patterns help to select appropriate empirical treatments of urinary tract infections (UTIs). This study aimed to investigate antibiotic resistance among Enterobacteriaceae isolated from UTIs in Azerbaijan, Iran. Methods: This study was carried out during 2016 in hospitals located in Tabriz, Urmia, and Khoy. Midstream urine specimens were cultured and identified by the standard methods. Susceptibility testing was carried out using the disk diffusion agar method for cefotaxime, ceftazidime, ceftriaxone, cefoxitin, imipenem, meropenem, ertapenem, cefepime, ampicillin, cefazolin, cefuroxime, aztreonam, nitrofurantoin, and fosfomycin and the agar dilution method for MIC determination of aminoglycosides, quinolones, sulfamethoxazole, and trimethoprim. Results: A total of 219 non-duplicated Enterobacteriaceae were isolated from UTIs. According to the agar dilution assay, the following resistance rates were determined: trimethoprim/sulfamethoxazole (co-trimoxazole) 69.8%, nalidixic acid 68.9%, ciprofloxacin 66.2%, levofloxacin 58.5%, tobramycin 47.9%, kanamycin 39.3%, gentamicin 27.8%, and amikacin 5.5%. High levels of resistance were observed to trimethoprim (78.5%), sulfamethoxazole (88.1%), ampicillin (86.3%), and cephazoline (79.4%). Conclusion: The most effective agents against Enterobacteriaceae were fosfomycin, carbapenems, and amikacin. Quinolones, trimethoprim and sulfamethoxazole are not appropriate for empirical therapy due to high levels of resistance. Amikacin is more effective among aminoglycosides and may be more effective, in complicated cases, when used in combination with fosfomycin and carbapenems.

The prevalence of plasmid-mediated quinolone resistance and ESBL-production in Enterobacteriaceae isolated from urinary tract infections.

INTRODUCTION: ß-lactam and fluoroquinolone antibiotics are usually used for the treatment of urinary tract infections (UTIs). The aim of this study was to determine the prevalence of plasmid-mediated quinolone resistance (PMQR) and extended spectrum ß-lactamases (ESBLs) in Enterobacteriaceae isolated from UTIs. MATERIALS AND METHODS: Two hundred and nineteen samples of Enterobacteriaceae isolated from UTIs were collected in the Northwest of Iran. Antimicrobial susceptibility testing was determined by the disk diffusion method. ESBLs were detected by the double-disk test. ESBL and PMQR-encoding genes were screened using the polymerase chain reaction. RESULTS: The rate of resistance to moxifloxacin, nalidixic acid, gatifloxacin, ofloxacin, ciprofloxacin, and levofloxacin in ESBL-producing isolates was 89.3%, 88%, 84%, 80%, 78.7%, and 73.3%, respectively. PMQR-producing Enterobacteriaceae isolates were identified in 67 samples (89.1%). The most prevalent PMQR genes were aac (6')-Ib-cr 120 (68.6%) followed by oqxB 72 (41.1%), oqxA 59 (33.7%), qnrB 36 (20.6%), qnrS 33 (18.9%), qnrD 19 (10.9%), qepA 13 (7.4 %), qnrA 10 (5.7%), and qnrC 9 (5.1%). There was a strong association between PMQR genes and blaCTX-M-15 and blaTEM-116 and other ESBL genes. CONCLUSION: High resistance rates were detected to quinolones among ESBL-producing isolates from UTIs. There is a high prevalence of PMQR genes in Enterobacteriaceae in Azerbaijan and Iran, and the most common PMQR is aac(6')-Ib-cr. There is a significant association between PMQR and ESBL-producing isolates.