Mutant prevention concentration of ozenoxacin for quinolone-susceptible or -resistant Staphylococcus aureus and Staphylococcus epidermidis

Ozenoxacin (OZN) belongs to a new generation of non-fluorinated quinolones for the topical treatment of skin infections which has shown to be effective in the treatment of susceptible and resistant Gram-positive cocci. The mutant prevention concentration (MPC) of ozenoxacin, levofloxacin and ciprofloxacin was determined in quinolone-susceptible and -resistant strains including methicillin-susceptible S. aureus, methicillin-resistant S. aureus, methicillin-susceptible S. epidermidis and methicillin-resistant S. epidermidis with different profile of mutation in the quinolone resistance determining regions (QRDR). The MPC value of OZN for the methicillin-susceptible S. aureus strain susceptible to quinolones, without mutations in QRDR, was 0.05 mg/L, being 280-fold lower than that observed with ciprofloxacin and levofloxacin. In methicillin-susceptible and-resistant S. aureus strains with mutations in the gyrA or/and grlA genes the MPC of OZN went from 0.1 to 6 mg/L, whereas the MPC of levofloxacin and ciprofloxacin was > 50 mg/L for the same strains. For methicillin-susceptible and-resistant S. epidermidis the results were similar to those abovementioned for S. aureus. According to our results, the MPC of OZN was far below the quantity of ozenoxacin achieved in the epidermal layer, suggesting that the in vivo selection of mutants, if it occurs, will take place at low frequency. Ozenoxacin is an excellent candidate for the treatment of bacterial infections caused by susceptible and quinolone-resistant staphylococci isolated usually from skin infections

Click reactions in the synthesis of tripodal 1H-1,2,3-triazol derivatives of 1,3,5-triazinane-2,4,6-trione

The 15th International Electronic Conference on Synthetic Organic Chemistry session General Organic SynthesisThe copper catalyzed Huisgen reaction was used for the synthesis of two derivatives of 1H-1,2,3-triazol-1,3,5-triazinane-2,4,6-trione. One from tris(2-azidoethyl)-1,3,5-triazinane-2,4,6-trione and phenylacetylene, and the other by coupling of 1,3,5-tri(prop-2-yn-1-yl)-1,3,5-triazinane-2,4,6-trione with benzyl azideXunta de Galicia for financial support: INCITE09 262346PR. X. F. thanks the Isidro Parga Pondal Program (Xunta de Galicia, Spain

Ozenoxacin: a review of preclinical and clinical efficacy

Introduction: Impetigo is the most common bacterial skin infection in children. Treatment is becoming complicated due to the development of antimicrobial resistance, especially in the main pathogen, Staphylococcus aureus. Ozenoxacin, a novel non-fluorinated topical quinolone antimicrobial, has demonstrated efficacy in impetigo. Areas covered: This article reviews the microbiology, pharmacodynamic and pharmacokinetic properties of ozenoxacin, and its clinical and microbiological efficacy in impetigo. Expert opinion: In an environment of increasing antimicrobial resistance and concurrent slowdown in antimicrobial development, the introduction of a new agent is a major event. Ozenoxacin is characterized by simultaneous affinity for DNA gyrase and topoisomerase IV, appears to be impervious to certain efflux pumps that confer bacterial resistance to other quinolones, shows low selection of resistant mutants, and has a mutant prevention concentration below its concentration in skin. These mechanisms protect ozenoxacin against development of resistance, while the absence of a fluorine atom in its structure confers a better safety profile versus fluoroquinolones. In vitro studies have demonstrated high potency of ozenoxacin against staphylococci and streptococci including resistant strains of S. aureus. Clinical trials of ozenoxacin in patients with impetigo reported high clinical and microbiological success rates. Preserving the activity and availability of ozenoxacin through antimicrobial stewardship is paramount

Comparative in vitro antibacterial activity of ozenoxacin against Gram-positive clinical isolates

AIM: To compare the in vitro activity of the anti-impetigo agent, ozenoxacin, and other antimicrobial agents against Gram-positive clinical isolates from skin and soft tissue infections. MATERIALS & METHODS: Isolates were collected in two studies: 1097 isolates from 49 centers during 2009-2010 and 1031 isolates from ten centers during 2014. Minimum inhibitory concentrations were determined for 18 and 11 antimicrobials in these studies, respectively, using standard broth microdilution methods. Isolates were stratified by species and methicillin susceptibility/resistance and/or levofloxacin susceptibility/nonsusceptibility status. RESULTS: Ozenoxacin exhibited high in vitro activity against Staphylococcus aureus and coagulase-negative staphylococci isolates in both studies. Ozenoxacin was also highly active against Streptococcus pyogenes and Streptococcus agalactiae isolates. CONCLUSION: Ozenoxacin is a potent antimicrobial agent against staphylococci and streptococci

Highly functionalized 2-oxopiperazine-based peptidomimetics: An approach to PAR1 antagonists

A series of pseudodipeptide-based chiral 1,3,4,5-tetrasubstituted-2- oxopiperazines has been designed and synthesized as potential PAR1 antagonists. These highly functionalized piperazines were synthesized from aromatic and basic amino acid derived Ψ[CH(CN)NH]pseudodipeptides through a four step pathway that involves reduction of the cyano group to build the 2-oxopiperazine ring, followed by selective functionalization at the N4-, N 1-positions, and at the exocyclic moiety at position C5. This regioselective functionalization required the fine tuning of reaction conditions. All new compounds were screened as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cell lines. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at μM concentration. No correlation was observed between both types of activities.Peer Reviewe

Plasticity, exudation and microbiome-association of the root system of Pellitory-of-the-wall plants grown in environments impaired in iron availability

The investigation of the adaptive strategies of wild plant species to extreme environments is a challenging issue, which favors the identification of new traits for plant resilience. We investigated different traits which characterize the root-soil interaction of Parietaria judaica, a wild plant species commonly known as "Pellitory-of-the-wall". P. judaica adopts the acidification-reduction strategy (Strategy I) for iron (Fe) acquisition from soil, and it can complete its life cycle in highly calcareous environments without any symptoms of chlorosis. In a field-to-lab approach, the microbiome associated with P. judaica roots was analyzed in spontaneous plants harvested from an urban environment consisting in an extremely calcareous habitat. Also, the phenolics and carboxylates content and root plasticity and exudation were analyzed in P. judaica plants grown under three different controlled conditions mimicking the effect of calcareous environments on Fe availability: results show that P. judaica differentially modulates root plasticity under different Fe availability-impaired conditions, and that it induces, to a high extent, the exudation of caffeoylquinic acid derivatives under calcareous conditions, positively impacting Fe solubility.13n

Phylogeography of hepatitis B virus: the role of Portugal in the early dissemination of HBV worldwide

Copyright: © 2022 Marcelino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.In Portugal, the genetic diversity, origin of HBV and the Portuguese role in the dissemination of HBV worldwide were never investigated. In this work, we studied the epidemic history and transmission dynamics of HBV genotypes that are endemic in Portugal. HBV pol gene was sequenced from 130 patients followed in Lisbon. HBV genotype A was the most prevalent (n = 54, 41.5%), followed by D (n = 44, 33.8%), and E (n = 32, 24.6%). Spatio-temporal evolutionary dynamics was reconstructed in BEAST using a Bayesian Markov Chain Monte Carlo method, with a GTR nucleotide substitution model, an uncorrelated lognormal relaxed molecular clock model, a Bayesian skyline plot, and a continuous diffusion model. HBV subgenotype D4 was the first to be introduced in Portugal around 1857 (HPD 95% 1699-1931) followed by D3 and A2 a few decades later. HBV genotype E and subgenotype A1 were introduced in Portugal later, almost simultaneously. Our results indicate a very important role of Portugal in the exportation of subgenotypes D4 and A2 to Brazil and Cape Verde, respectively, in the beginning of the XX century. This work clarifies the epidemiological history of HBV in Portugal and provides new insights in the early and global epidemic history of this virus.This work was performed in the context of Rute Marcelino PhD study, whose student’s fellowship (SFRH/BD/99507/2014) was supported by the Portuguese Agency for Scientific Research, Fundação para a Ciência e Tecnologia (FCT), POCH program, Portugal 2020, and European Union/Social European Fund (FSE). This work was also supported by FCT through funds of AA's projects GHTM-UID/Multi/04413/2013 and GHTM-UID/04413/2020 and also NT's projects UIDB/04138/2020 and UIDP/04138/2020.info:eu-repo/semantics/publishedVersio

Ancestry Analysis in the 11-M Madrid Bomb Attack Investigation

The 11-M Madrid commuter train bombings of 2004 constituted the second biggest terrorist attack to occur in Europe after Lockerbie, while the subsequent investigation became the most complex and wide-ranging forensic case in Spain. Standard short tandem repeat (STR) profiling of 600 exhibits left certain key incriminatory samples unmatched to any of the apprehended suspects. A judicial order to perform analyses of unmatched samples to differentiate European and North African ancestry became a critical part of the investigation and was instigated to help refine the search for further suspects. Although mitochondrial DNA (mtDNA) and Y-chromosome markers routinely demonstrate informative geographic differentiation, the populations compared in this analysis were known to show a proportion of shared mtDNA and Y haplotypes as a result of recent gene-flow across the western Mediterranean, while any two loci can be unrepresentative of the ancestry of an individual as a whole. We based our principal analysis on a validated 34plex autosomal ancestryinformative-marker single nucleotide polymorphism (AIM-SNP) assay to make an assignment of ancestry for DNA from seven unmatched case samples including a handprint from a bag containing undetonated explosives together with personal items recovered from various locations in Madrid associated with the suspects. To assess marker informativeness before genotyping, we predicted the probable classification success for the 34plex assay with standard error estimators for a naı¨ve Bayesian classifier using Moroccan and Spanish training sets (each n = 48). Once misclassification error was found to be sufficiently low, genotyping yielded seven near-complete profiles (33 of 34 AIM-SNPs) that in four cases gave probabilities providing a clear assignment of ancestry. One of the suspects predicted to be North African by AIM-SNP analysis of DNA from a toothbrush was identified late in the investigation as Algerian in origin. The results achieved illustrate the benefit of adding specialized marker sets to provide enhanced scope and power to an already highly effective system of DNA analysis for forensic identification.European Commission GROWTH program, SNPforID project, contract G6RD-CT-2002-00844 to CP. Xunta de Galicia, Spain: Fund PGIDTIT06PXIB228195PR and Ministerio de Educación y Ciencia, Spain: project BIO2006-06178 to MVL. Fundación de Investigación Médica Mutua Madrileña, Spain: 2006/CL370 and 2008/CL444 to AS. Continued development of the work and its application to forensic analysis is being funded by Allelyus, Santiago de Compostela, SpainS

Molecular Profiling of Circulating Tumour Cells Identifies Notch1 as a Principal Regulator in Advanced Non-Small Cell Lung Cancer

Knowledge on the molecular mechanisms underlying metastasis colonization in Non-Small Cell Lung Cancer (NSCLC) remains incomplete. A complete overview integrating driver mutations, primary tumour heterogeneity and overt metastasis lacks the dynamic contribution of disseminating metastatic cells due to the inaccessibility to the molecular profiling of Circulating Tumour Cells (CTCs). By combining immunoisolation and whole genome amplification, we performed a global gene expression analysis of EpCAM positive CTCs from advanced NSCLC patients. We identified an EpCAM+ CTC-specific expression profile in NSCLC patients mostly associated with cellular movement, cell adhesion and cell-to-cell signalling mediated by PI3K/AKT, ERK1/2 and NF-kB pathways. NOTCH1 emerged as a driver connecting active signalling pathways, with a reduced number of related candidate genes (NOTCH1, PTP4A3, LGALS3 and ITGB3) being further validated by RT-qPCR on an independent cohort of NSCLC patients. In addition, these markers demonstrated high prognostic value for Progression-Free Survival (PFS). In conclusion, molecular characterization of EpCAM+ CTCs from advanced NSCLC patients provided with highly specific biomarkers with potential applicability as a “liquid biopsy” for monitoring of NSCLC patients and confirmed NOTCH1 as a potential therapeutic target to block lung cancer dissemination.This work was funded by InveNNta (Innovation in Nanomedicine); Operational Programme for Cross-border Cooperation: Spain-Portugal (POCTEP) and European Regional Development Fund (ERDF). Javier Mariscal is recipient of a fellowship from Escola de Doutoramento Internacional Campus Vida of the University of Santiago de Compostela. Laura Muinelo-Romay is supported by ISCIII as Responsible of the Liquid Biopsy Analysis UnitS