Multidrug-resistant Ones Research Articles

Peculiarities of clabsi in oncologic hospitals

Currently, healthcare-associated infections (HAIs) are one of the most dangerous complications for hospitalized patients. The economic damage caused by HCAI in the Russian Federation annually is about 15 billion rubles; in addition, HCAI occupy the tenth place among the causes of mortality of the population. Catheter-associated bloodstream infection holds the leading place in the structure of ISMP morbidity. The concept of CVC-AIC (catheter-associated bloodstream infections or CLABSI), in turn, is included in CAIC. Purpose of the study. To analyze the current literature data of domestic and foreign authors for the years 2012-2022 concerning CAIC in patients of oncologic hospitals with CVCs, including subcutaneous central venous port catheters. Material and Methods. A review of 38 literature sources for the last 10 years was performed, including current information on catheter-associated bloodstream infections, measures to prevent them, and modern treatment approaches. Results. The studies have shown that the combination of drug resistance in microorganisms and immunity reduction in cancer patients, which occurs against the background of chemotherapy, makes them a risk group for the development of CAICs and episodes of their recurrence. Ensuring epidemiological safety of bloodstream catheterization in such patients is an important step in the prevention of CAIC. This is one of the priority tasks of oncoepidemiology today. Conclusion. The leading role in the occurrence of catheter-associated bleeding plays the term of catheterization and the condition of the patient, his age, stage of cancer development and concomitant chronic diseases. One of the most vulnerable risk groups are cancer patients from hemoblastosis chemotherapy and bone marrow and hematopoietic stem cell transplantation units. This may be due to the use of immunosuppressant drugs to suppress graft rejection, which significantly reduce patients' immunity. According to the results of studies, infection with drug-resistant Gram-negative microorganisms, including multidrug-resistant ones, is prevalent in cancer patients with CAIC. When using povidone iodine, there is a tendency to decrease the incidence of CAIC, but the use of chlorhexidine alcohol solution showed better results. A direct correlation was observed between the use of surgically implanted intravascular devices for long-term function and a lower incidence of CAIC, particularly in pediatric oncology.

Pyrrole-Based Enaminones as Building Blocks for the Synthesis of Indolizines and Pyrrolo[1,2-a]pyrazines Showing Potent Antifungal Activity.

As a new approach, pyrrolo[1,2-a]pyrazines were synthesized through the cyclization of 2-formylpyrrole-based enaminones in the presence of ammonium acetate. The enaminones were prepared with a straightforward method, reacting the corresponding alkyl 2-(2-formyl-1H-pyrrol-1-yl)acetates, 2-(2-formyl-1H-pyrrol-1-yl)acetonitrile, and 2-(2-formyl-1H-pyrrol-1-yl)acetophenones with DMFDMA. Analogous enaminones elaborated from alkyl (E)-3-(1H-pyrrol-2-yl)acrylates were treated with a Lewis acid to afford indolizines. The antifungal activity of the series of substituted pyrroles, pyrrole-based enaminones, pyrrolo[1,2-a]pyrazines, and indolizines was evaluated on six Candida spp., including two multidrug-resistant ones. Compared to the reference drugs, most test compounds produced a more robust antifungal effect. Docking analysis suggests that the inhibition of yeast growth was probably mediated by the interaction of the compounds with the catalytic site of HMGR of the Candida species.

Microbial Complexity of Oral Cavity of Healthy Dogs Identified by Mass Spectrometry and Next-Generation Sequencing.

The high complexity of the oral microbiota of healthy dogs and the close exposure of humans to companion animals represent a risk of the transmission of potential zoonotic microorganisms to humans, especially through dog bites, including multidrug-resistant ones. Nonetheless, a limited number of comprehensive studies have focused on the diversity of the microorganisms that inhabit the oral cavities of healthy dogs, particularly based on modern molecular techniques. We investigated bacterial and fungal organisms in the oral cavities of 100 healthy dogs based on a combination of conventional and selective microbiological culture, mass spectrometry (MALDI-TOF MS), and next-generation sequencing. In addition, in vitro antimicrobial susceptibility patterns of isolates and mecA resistance gene were assessed. A total of 213 bacteria and 20 fungi were isolated. Staphylococcus pseudintermedius (40/100 = 40%), α-hemolytic Streptococcus (37/100 = 37%), and Pasteurella stomatis (22/100 = 22%) were the most prevalent bacteria diagnosed by microbiological culture and MALDI-TOF MS, whereas Aspergillus (10/100 = 10%) was the most common fungi identified. Based on next-generation sequencing of selected 20 sampled dogs, Porphyromonas (32.5%), Moraxella (16.3%), Fusobacterium (12.8%), Conchiformibius (9.5%), Bergeyella (5%), Campylobacter (3.8%), and Capnocytophaga (3.4%) genera were prevalent. A high multidrug resistance rate was observed in Staphylococcus pseudintermedius isolates, particularly to azithromycin (19/19 = 100%), penicillin (15/19 = 78.9%), and sulfamethoxazole/trimethoprim (15/19 = 78.9%). In addition, the mecA resistance gene was detected in 6.1% (3/49) of coagulase-positive staphylococci. Here, we highlight the microbial complexity of the oral mucosa of healthy dogs, including potential zoonotic microorganisms and multidrug-resistant bacteria, contributing with the investigation of the microbiota and antimicrobial resistance patterns of the microorganisms that inhabit the oral cavity of healthy dogs.

Biochemical and Antioxidant Properties as well as Antimicrobial and Antibiofilm Activities of Allium scorodoprasum subsp. jajlae (Vved.) Stearn.

In this study, the chemical composition and biological activity of Allium scorodoprasum subsp. jajlae (Vved.) Stearn were investigated for the first time, focusing on its antimicrobial, antioxidant, and antibiofilm properties. A GC-MS analysis was employed to evaluate the composition of its secondary metabolites, identifying linoleic acid, palmitic acid, and octadecanoic acid 2,3-dihydroxypropyl ester as the major compounds in ethanol extract. The antimicrobial activity of A. scorodoprasum subsp. jajlae was assessed against 26 strains, including standard, food isolate, clinical isolate, and multidrug-resistant ones, as well as three Candida species using the disc diffusion method and the determination of the minimum inhibitory concentration (MIC). The extract showed strong antimicrobial activity against Staphylococcus aureus strains, including methicillin-resistant and multidrug-resistant strains, as well as Candida tropicalis and Candida glabrata. Its antioxidant capacity was evaluated using the DPPH method, revealing a high level of antioxidant activity in the plant. Additionally, the antibiofilm activity of A. scorodoprasum subsp. jajlae was determined, demonstrating a reduction in biofilm formation for the Escherichia coli ATCC 25922 strain and an increase in biofilm formation for the other tested strains. The findings suggest potential applications of A. scorodoprasum subsp. jajlae in the development of novel antimicrobial, antioxidant, and antibiofilm agents.

Molecular identification and antimicrobial resistance pattern of Nocardia isolated from 14 diseased dogs and cats.

Nocardia are ubiquitous, saprophytic and opportunistic bacteria. They cause a set of pyogenic clinical infections in animals and humans, particularly immunocompromised patients, mostly affecting the skin and respiratory tract, with refractoriness to conventional therapy. The most descriptions of nocardial infections in companion animals involve case reports, and there are scarce case series studies focused on canine and feline nocardiosis in which diagnosis has been based on molecular techniques. We investigated epidemiological aspects, clinical findings, in vitro susceptibility profile, and molecular identification of Nocardia using PCR-based method targeted 16S rRNA gene in twelve dogs and two cats. Among dogs were observed cutaneous lesions (8/12 = 67%), pneumonia (3/12 = 25%), and encephalitis (2/12 = 17%), whereas cats developed cutaneous lesions and osteomyelitis. Nocardia and canine morbillivirus coinfection was described in six dogs (6/12 = 50%). A high mortality rate (6/8 = 75%) was seen among dogs. Three dogs (3/4 = 75%) and one cat (1/2 = 50%) with systemic signs (pneumonia, encephalitis, osteomyelitis), and 83% (5/6) of dogs with a history of concomitant morbillivirus infection died. N. nova (5/12 = 42%), N. cyriacigeorgica (3/12 = 25%), N. farcinica (2/12 = 17%), N. veterana (1/12 = 8%), and N. asteroides (1/12 = 8%) species were identified in dogs, whereas N. africana and N. veterana in cats. Among the isolates from dogs, cefuroxime (12/12 = 100%), amikacin (10/12 = 83%), gentamycin (10/12 = 83%), and imipenem (10/12 = 83%) were the most effective antimicrobials, whereas cefuroxime, cephalexin, amoxicillin/clavulanic acid, imipenem, and gentamycin were efficient against isolates from cats. Multidrug resistance was observed in 36% (5/14) of isolates. We describe a variety of Nocardia species infecting dogs and cats, multidrug-resistant ones, and a high mortality rate, highlighting a poor prognosis of nocardiosis in companion animals, particularly among animals systemically compromised or coinfected by canine morbillivirus. Our study contributes to species identification, in vitro antimicrobial susceptibility profile, clinical-epidemiological aspects, and outcome of natural Nocardia-acquired infections in dogs and cats.

Association between antimicrobial resistance and biofilm forming ability of Salmonella enterica serotypes from commercial broiler farms in Brazil

ABSTRACT 1. This study determined the antimicrobial resistance profile and the biofilm-forming ability of Salmonella enterica strains isolated from commercial broiler houses over a three-year period in southern Brazil. 2. Of the 720 drag swabs analysed, 37 (5%) tested positive for non-typhoidal Salmonella spp. and S. Heidelberg was the most frequent serovar. 3. Among the antimicrobial resistant strains (83.8%; 31/37), resistance was most common to tetracycline, ampicillin and nalidixic acid. Multidrug resistance was found in 65% (24/37) of the isolates, with a large proportion of multidrug resistant S. Heidelberg strains (81%; 13/16). 4. In total, 65% (24/37) of the isolates showed the ability to produce biofilm and multiple antimicrobial resistance was negatively correlated with biofilm formation. 5. Strains susceptible to all tested antimicrobials tended to form stronger biofilms than multidrug resistant ones. This suggested that Salmonella spp. with less antimicrobial resistance depend more on the protection provided by biofilm to survive in the farm environment.

The efficiency of metal, metal oxide, and metalloid nanoparticles against cancer cells and bacterial pathogens: different mechanisms of action

The applications of nanoparticles in various practical fields, owing to their unique properties compared with bulk materials, have been occupying the minds of scientists for several decades. In this regard, a combination of pharmacology and nanotechnology has contributed to producing newer effective anticancer and antimicrobial agents to inactivate resistant cancer cells and microorganisms, specifically multidrug-resistant ones. The physicochemical properties of nanoparticles based on metalloid, metal, and metal oxides such as selenium, silver, gold, titanium dioxide, zinc oxide, copper oxide, platinum, and magnesium oxide, have been well known and referred to as anticancer and antimicrobial agents or carriers. The inactivation and eradication of Gram-positive and Gram-negative bacteria may be mainly resulted from the oxidative damages in the bacterial medium. Overall, metalloid, metal and metal oxide NPs can be functionalized by other antibacterial or anticancer agents and biocompatible stabilizers to increase their efficiency in physiological conditions. However, the undesirable cytotoxicity of these nanoparticles in physiological conditions is the major hindrance to their application in the pharmaceutical industry and therapeutics. Nevertheless, it is expected that these problems will be solved in the near future. Therefore, the main objective of this review is to report an overview of the recent signs of progress in increasing anticancer and antibacterial mechanisms of metal and metal-based nanoparticles.

Biosynthesis of selenium nanoparticles using combinations of plant extracts and their antibacterial activity

Antimicrobial resistance is a significant public health problem, and the use of nanotechnology to control bacterial growth has increased, including multidrug-resistant ones. In this context, nanoparticles of different elements, mainly metals, such as silver, gold, and iron, have been extensively researched due to their efficient antimicrobial activity. Another element that stands out is selenium, which nanoparticles have high bioactivity and antibacterial action, although few studies report its use as a metallic nanoparticle. Therefore, the objective of this study was to perform the synthesis of selenium nanoparticles (SeNPs) from extracts of three plants: Allium cepa (onion), Malpighia emarginata (acerola), and Gymnanthemum amygdalinum (boldo). The synthesized nanoparticles were characterized by Dynamic Light Scattering (DLS), scanning electron microscopy (SEM), Fourier-Transform Infrared Spectroscopy (FTIR) and X-Ray Diffraction (DRX). Antibacterial activity was evaluated by microdilution in broth, followed by the time-kill curve analysis. The bacterial strains tested were Streptococcus agalactiae, Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeruginosa, and Escherichia coli. Hemolytic activity was also determined. The synthesized SeNPs had a size between 245 and 321 ​nm and mostly spherical morphology. Antimicrobial activity against all Gram-positive bacteria tested was observed, with minimal inhibitory concentrations ranging from 6.125 to 98 ​μg/ml, but without action in the tested Gram-negative bacteria. Low hemolytic capacity was observed, with CC50 ranging from 0.82 to 2.1 ​mg/ml. The antimicrobial activity and low hemolytic concentration indicate the possibility of use against Gram-positive bacteria, including multidrug-resistant ones, opening a wide variety of options for their applications.

Ag-Doped and Antibiotic-Loaded Hexagonal Boron Nitride Nanoparticles as Promising Carriers to Fight Different Pathogens.

Utilization of antibacterial components-conjugated nanoparticles (NPs) is emerging as an attractive strategy for combating various pathogens. Herein, we demonstrate that Ag/BN NPs and antibiotic-loaded BN and Ag/BN nanoconjugates are promising carriers to fight bacterial and fungal infections. Extensive biological tests included two types of Gram-positive methicillin-resistant Staphylococcus aureus strains (B8469 and MW2), two types of Gram-negative Pseudomonas aeruginosa strains (ATCC27853 and B1307/17), and 47 types of Escherichia coli strains (including 41 multidrug-resistant ones), as well as five types of fungal cultures: Candida albicans (candidiasis-thrush) ATCC90028 and ATCC24433, Candida parapsilosis ATCC90018, Candida auris CBS109113, and Neurospora crassa wt. We have demonstrated that, even within a single genus Escherichia, there are many hospital E. coli strains with multi-drug resistance to different antibiotics. Gentamicin-loaded BN NPs have high bactericidal activity against S. aureus, P. aeruginosa, and 38 types of the E. coli strains. For the rest of the tested E. coli strains, the Ag nanoparticle-containing nanohybrids have shown superior bactericidal efficiency. The Ag/BN nanohybrids and amphotericin B-loaded BN and Ag/BN NPs also reveal high fungicidal activity against C. albicans, C. auris, C. parapsilosis, and N. crassa cells. In addition, based on the density functional theory calculations, the nature of antibiotic-nanoparticle interaction, the sorption capacity of the BN and Ag/BN nanohybrids for gentamicin and amphotericin B, and the most energetically favorable positions of the drug molecules relative to the carrier surface, which lead to lowest binding energies, have been determined. The obtained results clearly show high therapeutic potential of the antibiotic-loaded Ag/BN nanocarriers providing a broad bactericidal and fungicidal protection against all of the studied pathogens.

A review on nanostructured silver as a basic ingredient in medicine: physicochemical parameters and characterization.

Recent studies with silver nanoparticles (AgNPs) and the history of silver metal as a broad-spectrum bactericidal and virucidal agent, places silver as one of the future biocidal candidates in the field of nanomedicine to eliminate bacteria and viruses, especially multidrug resistant ones. In this review, we have described the various morphologies of AgNPs and correlated the enhanced bactericidal activity with their prominent {111} facets. In addition to prioritizing the characterization we have also discussed the importance of quantifying AgNPs and silver ion content (Ag+) and their different mechanisms at the chemical, biological, pharmacological, and toxicological levels. The mechanism of action of AgNPs against various bacteria and viruses including the SARS-CoV-2 was analyzed in order to understand its effectiveness as an antimicrobial agent with therapeutic efficacy and low toxicity. Further, there is the need to characterize AgNPs and quantify the content of free Ag+ for the implementation of new systematic studies of this promising agent in nanomedicine and in clinical practice.

Nanotechnologies in the Light of Modern Antibacterial Strategies: A Review

Introduction: The emergence and growth of multidrug-resistant (MDR) bacterial strains in recent decades is associated with the widespread and uncontrolled use of antibiotics, as well as a decrease in the number of effective studies and discoveries of new classes of antibacterial drugs. These alarming trends are recognized as a major threat to global public health. They stimulate and increase the relevance of a large-scale search and study of new antimicrobial strategies, alternative to traditional antibiotic therapy. The purpose of the review is a critical analysis of advantages and limitations of modern antimicrobial platforms with an emphasis on innovative techniques of using nanoparticles for a direct or indirect effect on pathogenic bacteria, including the MDR ones. Materials and methods: The search for literary sources published in 2017–2021 was carried out in the resources of the Cochrane Library (Wiley Online Library directory), EMBASE (EMBASE.com), CINAHL, and Web of Science. Results: Most positive therapeutic effects for the diagnosis and treatment of infectious diseases were obtained by implementing fundamentally new mechanisms of antimicrobial activity of nanosized particles and other nanomaterials. When assessing future prospects of nanotechnology as the most dynamically and actively developing and promising recent antimicrobial strategy, it should be concluded that these innovative platforms certainly merit attention and further study as alternative means of preventing and treating bacterial infections. The main limitation for the clinical use of modern nanomaterials is the need for further assessment of their safety and cytotoxicity. Conclusions: Tackling antibiotic resistance requires the concerted action of community and government institutions. The development of safe and effective antibacterial technologies should be accompanied by adoption of an international program of strict regulation and tough measures of control over validity and rational use of antibiotics and other antibacterial drugs in medicine, cosmetology, and agriculture.

Immunological detection of AcAMP antimicrobial peptide secreted by Aspergillus clavatus.

Background and Objectives:Aspergillus clavatus antimicrobial peptide (AcAMP) is a fungi-derived peptide with a broad spectrum of activity against pathogenic bacteria and fungi. Natural antimicrobial peptides, including AcAMP, have attracted many attentions in the development of new natural antibiotics against pathogenic bacteria, especially multidrug resistant ones.Materials and Methods:In the present study, acamp gene was codon-optimized and chemically synthesized in pUC57 cloning vector, subcloned into pET28a (+) expression vector and transferred into competent Escherichia coli BL21 (DE3) cells. The expression of AcAMP was induced by addition of Isopropyl β- d-1-thiogalactopyranoside (IPTG) and the expressed peptide was purified by Ni-NTA. BALB/c mice were immunized with the purified peptide and the ability of the immunized mice sera for the detection of the native AcAMP secreted by A. clavatus IRAN 142C was examined through ELISA and Western blotting techniques.Results:Both ELISA and Western blotting demonstrated the ability of the sera of the immunized mice to detect the native AcAMP.Conclusion:The results of the present work show that the raised antibody against recombinant AcAMP can be used to detect AcAMP peptide, an issue which paves the way to develop detection kits for the detection of AcAMP-producing organisms, purification of this valuable peptide for further investigations.

Nosocomial Pneumonia in the Era of Multidrug-Resistance: Updates in Diagnosis and Management.

Nosocomial pneumonia (NP), including hospital-acquired pneumonia in non-intubated patients and ventilator-associated pneumonia, is one of the most frequent hospital-acquired infections, especially in the intensive care unit. NP has a significant impact on morbidity, mortality and health care costs, especially when the implicated pathogens are multidrug-resistant ones. This narrative review aims to critically review what is new in the field of NP, specifically, diagnosis and antibiotic treatment. Regarding novel imaging modalities, the current role of lung ultrasound and low radiation computed tomography are discussed, while regarding etiological diagnosis, recent developments in rapid microbiological confirmation, such as syndromic rapid multiplex Polymerase Chain Reaction panels are presented and compared with conventional cultures. Additionally, the volatile compounds/electronic nose, a promising diagnostic tool for the future is briefly presented. With respect to NP management, antibiotics approved for the indication of NP during the last decade are discussed, namely, ceftobiprole medocaril, telavancin, ceftolozane/tazobactam, ceftazidime/avibactam, and meropenem/vaborbactam.

Antibiotic Susceptibility and Molecular Characterization of Uropathogenic Escherichia coli Associated with Community-Acquired Urinary Tract Infections in Urban and Rural Settings in South Africa.

We investigated the phenotypic and genotypic antibiotic resistance, and clonality of uropathogenic Escherichia coli (UPEC) implicated in community-acquired urinary tract infections (CA-UTIs) in KwaZulu-Natal, South Africa. Mid-stream urine samples (n = 143) were cultured on selective media. Isolates were identified using the API 20E kit and their susceptibility to 17 antibiotics tested using the disk diffusion method. Extended-spectrum β-lactamases (ESBLs) were detected using ROSCO kits. Polymerase chain reaction (PCR) was used to detect uropathogenic E. coli (targeting the papC gene), and β-lactam (blaTEM/blaSHV-like and blaCTX-M) and fluoroquinolone (qnrA, qnrB, qnrS, gyrA, parC, aac(6’)-Ib-cr, and qepA) resistance genes. Clonality was ascertained using ERIC-PCR. The prevalence of UTIs of Gram-negative etiology among adults 18–60 years of age in the uMgungundlovu District was 19.6%. Twenty-six E. coli isolates were obtained from 28 positive UTI samples. All E. coli isolates were papC-positive. The highest resistance was to ampicillin (76.9%) and the lowest (7.7%) to amoxicillin/clavulanic acid and gentamycin. Four isolates were multidrug-resistant and three were ESBL-positive, all being CTX-M-positive but SHV-negative. The aac(6’)-Ib-cr and gyrA were the most detected fluoroquinolone resistance genes (75%). Isolates were clonally distinct, suggesting the spread of genetically diverse UPEC clones within the three communities. This study highlights the spread of genetically diverse antibiotic-resistant CA-UTI aetiologic agents, including multidrug-resistant ones, and suggests a revision of current treatment options for CA-UTIs in rural and urban settings.

Constituents and antibacterial activity of leaf essential oil of Plectranthus scutellarioides

This study covers chemical profiling of leaf essential oil of Plectranthus scutellarioides (L.) R.Br along with the first report on its antibacterial activity. The extraction was performed by microwave assisted hydrodistillation where the yield of essential oil was 0.18%. A total of 28 constituents were separated and identified by gas chromatography mass spectrometry. The constituents that occurred in abundance were spathulenol (24.57%), D-germacrene (14.53%), bicyclogermacrene (11.24%), nonacosane (9.74%) and morillol (4.95%). The antibacterial evaluation of essential oil was carried out against 8 different gram negative and positive strains including multidrug-resistant ones with agar well diffusion method and macrodilution method and was found to be active against all strains. The strongest activity (MIC) was found against multidrug resistant strains of Escherichia coli (0.625 mg/mL) and methicillin resistant Staphylococcus aureus (2.5 mg/mL) that shows the potential of this essential oil.

Antibacterial and antitumor activity of the species Prunella vulgaris L.

Abstract Background: Prunella vulgaris L., known as self-healing herb, is a widely spread species in the spontaneous flora with beneficial effects on human health, a fact proven in particular by Asian researchers. The aim of this study was to evaluate the antitumor activity and the antibacterial effect on different bacterial strains, including multidrug-resistant ones, depending on the type of solvent used (aqueous, hydroalcoholic), the plant product taken into consideration (spike inflorescence, leaf), its quantity and the concentration of active principles. Material and method: For screening of antimicrobial susceptibility, both minimum inhibitory concentration and minimum bactericidal concentration were determined on Escherichia coli, Klebsiella pneumoniae, Providencia stuartii, Pseudomonas aeruginosai, and methicillin-resistant Staphylococcus aureus species, including reference strains and hospital strains. Leaves and flower extracts (aqueous and 70% methanolic) were first assessed, and the one with the best antibacterial potential was further tested as a concentrated extract. The antitumor activity was determined on MDA-MB-231 breast adenocarcinoma cells and on a non-tumor cell line, MCF-10A breast epithelial cells by means of Alamar blue technique and Scratch assay. Results: Inflorescence extracts showed better bacteriostatic effects than leaf extracts on most bacteria, in both aqueous and hydroalcoholic extracts. The concentrated extract of spike inflorescence showed measurable activity with good effects on Gram-positive bacteria, but also on multidrug-resistant Gram-negative ones. The 70% methanolic extract of the species Prunella vulgaris L. (spike inflorescence) demonstrated a concentration-dependent cytotoxic and anti-migratory activity on MDA-MB-231 breast cancer cells, while affecting the non-tumor cell line less. Conclusions: The results suggest that Prunella vulgaris extracts present antibacterial potential in the complementary treatment of multidrug-resistant infections. The extract from the spike inflorescence of Prunella vulgaris L. produced a dose and time-dependent reduction in cell viability and migration, eliciting a stronger effect on the breast adenocarcinoma cell line.

In vitro anti-leukemia activity of dual PI3K/mTOR inhibitor Voxtalisib on HL60 and K562 cells, as well as their multidrug resistance counterparts HL60/ADR and K562/A02 cells

Current treatment strategies for leukemia still have some limitations such as severe side effects and drug resistance. Less toxic and more effective drugs for leukemia patients are therefore expected. In the present study, the efficacy of a dual PI3K/mTOR inhibitor, Voxtalisib, on acute myeloid leukemia (AML) cell line HL60 and chronic myeloid leukemia (CML) cell line K562, as well as their Adriamycin (ADR)-selected multi drug resistance (MDR) counterparts HL60/ADR and K562/A02, was investigated. Voxtalisib exhibited potent anti-proliferative activity on these four cell lines dose-dependently, with IC50 values as 2.23 μM for HL60, 4.79 μM for HL60/ADR, 4.20 μM for K562 and 3.90 μM for K562/A02 cells. Voxtalisib arrested cell cycle progression at G1 phase in all cell lines by upregulating p27, downregulating cyclin D1 and p-pRb. When combined with ADR, Voxtalisib reversed the ADR-resistance of HL60/ADR and K562/A02 cells, possibly by reducing MDR1 and MRP1 expression. In conclusion, Voxtalisib showed anti-leukemia activity on AML and CML cell lines as well as their multidrug resistant ones, suggesting Voxtalisib might become a promising drug candidate for therapy of AML and CML in the future.

Synthesis, Self-Assembly, and Biomedical Applications of Antimicrobial Peptide-Polymer Conjugates.

Antimicrobial peptides (AMPs) have been attracting much attention due to their excellent antimicrobial efficiency and low rate in driving antimicrobial resistance (AMR), which has been increasing globally to alarming levels. Conjugation of AMPs into functional polymers not only preserves excellent antimicrobial activities but reduces the toxicity and offers more functionalities, which brings new insight toward developing multifunctional biomedical materials such as hydrogels, polymer vesicles, polymer micelles, and so forth. These nanomaterials have been exhibiting excellent antimicrobial activity against a broad spectrum of bacteria including multidrug-resistant (MDR) ones, high selectivity, and low cytotoxicity, suggesting promising potentials in wound dressing, implant coating, antibiofilm, tissue engineering, and so forth. This Perspective seeks to highlight the state-of-the-art strategy for the synthesis, self-assembly, and biomedical applications of AMP-polymer conjugates and explore the promising directions for future research ranging from synthetic strategies, multistage and stimuli-responsive antibacterial activities, antifungi applications, and potentials in elimination of inflammation during medical treatment. It also will provide perspectives on how to stem the remaining challenges and unresolved problems in combating bacteria, including MDR ones.

Abstract 5106: In vitro and in vivo evaluation of WAC-224, a novel quinolone class of topoisomerase II inhibitor for cancer therapy

Abstract Introduction: DNA topoisomerases (Topo) are classical but still attractive targets for drug therapy in multiple types of cancers. Topo inhibitors, such as Etoposide and Daunorubicin, have been effectively used; however, their clinical use is often limited by drug resistance in cancer cell population. Therefore, the development of a novel chemical class of Topo inhibitors has been desired to overcome drug resistance. Recently, Vosaroxin (QINPREZO) is identified as a first-in-class anti-cancer quinolone derivative targeting Topo II, which is under development for relapsed or refractory acute myeloid leukemia (AML). In this study, we evaluated the in vitro and in vivo activities of WAC-224, a novel quinolone derivative for Topo II inhibition, for various cancer cell lines including multi-drug resistant cells and in mouse xenograft models, respectively. Materials and Methods: In vitro anti-proliferative activities against over 20 cell lines were determined using WST cell proliferation reagent. Apoptosis was measured by Annexin-V staining. In vivo anti-tumor activity was determined in immunodeficient mice bearing multi-drug resistant human uterine sarcoma MES-SA/DX5. Results: WAC-224 accomplished extensive anti-proliferative activities for cancer cell lines including multi-drug resistant ones with the EC50 range of 0.001 to 1 microM. Especially, in MV4-11 AML cell line, WAC-224 showed a potent and superior anti-proliferative activity compared with Doxorubicin (EC50: 1.4 nM for WAC-224 v.s. 2.5 nM for Doxorubicin). Molecular and cellular mechanisms of WAC-224 were defined as inhibition of human Topo II, induction of G2/M phase cell cycle arrest and apoptosis. Additionally, significant antitumor effects of WAC-224 were confirmed in mouse xenograft models. Furthermore, WAC-224 showed no toxic effect on small intestinal crypts in mice. Conclusion: This study demonstrated that WAC-224 has strong in vitro activities against broad cancer cell types along with the potent in vivo efficacy and well tolerability, without gastrointestinal toxicity. These results indicate that WAC-224 is promised to provide a new therapeutic option for various cancers including multi-drug resistant and hematological ones. Citation Format: Taichi Ueshima, Tomonori Yamaguchi, Kenji Itoh, Naoki Kashimoto, Tatsuya Hirano, Rumiko Shimabara, Yohei Kawakubo, Masayuki Sato, Junpei Yamashita, Akira Yazaki, Koichi Tamura. In vitro and in vivo evaluation of WAC-224, a novel quinolone class of topoisomerase II inhibitor for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5106. doi:10.1158/1538-7445.AM2017-5106

Synthesis and Characterization of Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Antibacterial Activity against Gram-Negative Bacteria

There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens and no target-mediated cross-resistance with fluoroquinolones. We report our research efforts aimed at expanding the antibacterial spectrum of this class of molecules toward difficult-to-treat Gram-negative pathogens. Physicochemical properties (polarity and basicity) were considered to guide the design process. Dibasic tetrahydropyran-based compounds such as 6 and 21 are potent inhibitors of both DNA gyrase and topoisomerase IV, displaying antibacterial activities against Gram-positive and Gram-negative pathogens (Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii). Compounds 6 and 21 are efficacious in clinically relevant murine infection models.