Synthesis and Evaluation of Novel Metacetamol Derivatives with Hydrazone Moiety as Anticancer and Antimicrobial Agents.

By exploiting the wide biological potential of the hydrazone scaffold, a series of hydrazone derivatives were synthesized, starting from N-(3-hydroxyphenyl)acetamide (metacetamol). The structures of the compounds were determined using IR, 1 H and 13 C-NMR, and mass spectroscopic methods. The obtained molecules (3 a-j) were evaluated for their anticancer potential against MDA-MB-231 and MCF-7 breast cancer cell lines. According to the CCK-8 assay, all tested compounds showed moderate to potent anticancer activity. Among them, N-(3-(2-(2-(4-nitrobenzylidene)hydrazinyl)-2-oxoethoxy)phenyl)acetamide (3 e) was found to be the most effective derivative with an IC50 value of 9.89 µM against MDA-MB-231 cell lines. This compound was further tested for its potential effects on the apoptotic pathway. Molecular docking studies was also carried out for 3 e in the colchicine binding pocket of tubulin. Additionally, compound 3 e also demonstrated effective antifungal activity, particularly against Candida krusei (MIC=8 µg/ml), indicating that nitro group at the 4th  position of the phenyl ring was the most preferable substituent for both cytotoxic and antimicrobial activity. Our preliminary findings suggest that compound 3 e could be exploited as a leading structure for further anticancer and antifungal drug development.

Resistance and heteroresistance to colistin among clinical isolates of Acinetobacter baumannii.

Colistin is one of the most effective alternatives for treating Acinetobacter baumannii infections. The aim of this study was to determine colistin resistance and heteroresistance rates in A. baumannii from clinical samples in Hacettepe University clinical microbiology laboratory between June 2016 and January 2017. A total of 200 isolates were included in the study. In vitro susceptibility to amikacin, gentamicin, ceftazidime, piperacillin/tazobactam, meropenem, ciprofloxacin, and tigecycline were determined by disk diffusion test. Most isolates were multiresistant as they exhibited resistance to aminoglycosides, ß-lactams, and fluoroquinolones. Colistin susceptibility was determined by broth microdilution (BMD) test (EUCAST standards) and was compared with E-test (bioMérieux, France) in 120 isolates. In 14 blood isolates that were susceptible to colistin (MIC ≤ 2 mg/L), heteroresistance was investigated with the population analysis profile (PAP) method. Overall resistance (n = 200) to colistin was 28% by BMD. Among the 120 isolates where the two tests were compared, resistance to colistin was 25.8% versus 4.2% with BMD and E-test, respectively. Three blood isolates (21.4%) were heteroresistant to colistin. With E-test, a majority of the resistant isolates are overlooked and in vitro susceptibility to colistin should be determined with broth dilution method. This is the first study in Turkey reporting heteroresistance in A. baumannii isolates by the PAP method and emphasizes the need to test for heteroresistance in relation to clinical outcome in serious infections due to A. baumannii.

Presence of OXA-48 Gene in a Clinical Isolate of Lactobacillus rhamnosus.

Lactobacilli are part of the microbiota and are also used as probiotics. However, in recent years they have been associated with invasive infections, especially bacteremia. Lactobacillus spp. are usually susceptible to penicillins, macrolides, and carbapenems, but Lactobacillus rhamnosus is intrinsically resistant to glycopeptides. The aim of this study was to determine the antimicrobial susceptibility profile and resistance mechanism of a clinical isolate of L. rhamnosus isolated from 10 sets of blood cultures of the same patient. The isolate was identified by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (Bruker Daltonics; BD, Bremen, Germany) and 16S rRNA gene sequencing. In vitro susceptibilities to penicillin, ampicillin, imipenem, vancomycin, erythromycin, clindamycin, and linezolid were determined with gradient test strips (bioMérieux, France) on Mueller-Hinton agar plates supplemented with 5% defibrinated horse blood and 20 mg/L ß-NAD. The isolate was resistant to vancomycin and imipenem. Polymerase chain reaction test was positive for blaOXA-48 and the presence of this carbapenemase was confirmed by gene sequencing. Although plasmid analysis suggested that the blaOXA-48 is chromosomal in this isolate, it is still an alarming finding for potential transmission of antibiotic resistance genes to other bacteria in the gut. To our knowledge, this is the first report of the presence of blaOXA-48 in a Lactobacillus spp. and has utmost importance as these bacteria are used as probiotics. The isolation of these bacteria from sterile body sites should not go unnoticed.

First Detection of Klebsiella pneumoniae Isolate Co-Harboring Fosfomycin Resistance Gene fosA3 and blactx-m Among Gram Negative Urine Isolates in a Turkish Hospital.

The most common gram-negative pathogens in urinary tract infections are Escherichia coli and Klebsiella pneumoniae. Therapy that is often empirical relies on local antibiotic resistance data, hence monitorization of antimicrobial resistance periodically in each hospital is a requirement. In this study, antibiotic susceptibility profiles of consecutive urinary isolates (E. coli [n = 235] and K. pneumoniae [n = 56]) of adult patients collected between February 2018 and February 2019 from inpatients in Hacettepe University Hospital were assessed. Isolates resistant to fosfomycin (minimum inhibitory concentration >32 mg/L) were further investigated for the presence of fosA, fosA3, and fosC2. Fosfomycin susceptibility was determined by agar dilution method. Broth microdilution method was performed for amikacin, gentamicin, ceftazidime, ceftriaxone, meropenem, ciprofloxacin, tigecycline, trimethoprim/sulfamethoxazole (TMP/SMX), colistin, and piperacillin/tazobactam (PIP/TAZ). PCR method was employed to investigate fosA, fosA3, fosC2, and blaCTX-M. Existence of fosA3 gene was confirmed by sequencing. Resistance rates to amikacin, gentamicin, ceftazidime, ceftriaxone, meropenem, ciprofloxacin, tigecycline, TMP/SMX, colistin, and PIP/TAZ were 2.7%, 18.5%, 25.4%, 33.0%, 3.4%, 45.4%, 2.4%, 43.6%, 6.2%, and 23.7%, respectively. Sixteen isolates (5.5%) were resistant to fosfomycin. Resistance was most frequently observed in K. pneumoniae (n = 9). fosA3 gene was detected in one fosfomycin-resistant K. pneumoniae isolate. This isolate also carried blaCTX-M. fosC2 and fosA genes could not be detected in any of the isolates. In this study, we report for the first time the existence of fosA3 in Turkey and its association with the blaCTX-M gene. As a result of increasing blaCTX-M producing Enterobacterales isolates globally, increase in fosfomycin resistance may be expected in near future.