Future Prospects for Neisseria gonorrhoeae Treatment

Gonorrhea is a sexually transmitted disease with a high morbidity burden. Incidence of this disease is rising due to the increasing number of antibiotic-resistant strains. Neisseria gonorrhoeae has shown an extraordinary ability to develop resistance to all antimicrobials introduced for its treatment. In fact, it was recently classified as a “Priority 2” microorganism in the World Health Organization (WHO) Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery and Development of New Antibiotics. Seeing as there is no gonococcal vaccine, control of the disease relies entirely on prevention, diagnosis, and, especially, antibiotic treatment. Different health organizations worldwide have established treatment guidelines against gonorrhea, mostly consisting of dual therapy with a single oral or intramuscular dose. However, gonococci continue to develop resistances to all antibiotics introduced for treatment. In fact, the first strain of super-resistant N.gonorrhoeae was recently detected in the United Kingdom, which was resistant to ceftriaxone and azithromycin. The increase in the detection of resistant gonococci may lead to a situation where gonorrhea becomes untreatable. Seeing as drug resistance appears to be unstoppable, new treatment options are necessary in order to control the disease. Three approaches are currently being followed for the development of new therapies against drug-resistant gonococci: (1) novel combinations of already existing antibiotics; (2) development of new antibiotics; and (3) development of alternative therapies which might slow down the appearance of resistances. N. gonorrhoeae is a public health threat due to the increasing number of antibiotic-resistant strains. Current treatment guidelines are already being challenged by this superbug. This has led the scientific community to develop new antibiotics and alternative therapies in order to control this disease

Present and future of Carbapenem-Resistant Enterobacteriaceae (CRE) infections / Beatriz Suay García and María Teresa Pérez Gracia.

Este artículo se ha publicado de forma definitiva en: https://www.mdpi.com/2079-6382/8/3/122Carbapenem-resistant Enterobacteriaceae (CRE) have become a public health threat worldwide. There are three major mechanisms by which Enterobacteriaceae become resistant to carbapenems: enzyme production, e ux pumps and porin mutations. Of these, enzyme production is the main resistance mechanism. There are three main groups of enzymes responsible for most of the carbapenem resistance: KPC (Klebsiella pneumoniae carbapenemase) (Ambler class A), MBLs (Metallo-ß-Lactamases) (Ambler class B) and OXA-48-like (Ambler class D). KPC-producing Enterobacteriaceae are endemic in the United States, Colombia, Argentina, Greece and Italy. On the other hand, the MBL NDM-1 is the main carbapenemase-producing resistance in India, Pakistan and Sri Lanka, while OXA-48-like enzyme-producers are endemic in Turkey, Malta, the Middle-East and North Africa. All three groups of enzymes are plasmid-mediated, which implies an easier horizontal transfer and, thus, faster spread of carbapenem resistance worldwide. As a result, there is an urgent need to develop new therapeutic guidelines to treat CRE infections. Bearing in mind the di erent mechanisms by which Enterobacteriaceae can become resistant to carbapenems, there are di erent approaches to treat infections caused by these bacteria, which include the repurposing of already existing antibiotics, dual therapies with these antibiotics, and the development of new ß-lactamase inhibitors and antibiotics

Detection and Characterization of Extended-Spectrum Beta-Lactamases-Producing Escherichia coli in Animals.

The detection of multidrug-resistant bacteria is a growing problem; however, the role of domesticated animals in the propagation of antimicrobial resistance has barely been studied. The aim of this study was to identify extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli strains in domestic animal feces to assess their antimicrobial resistance profile and carry out molecular characterization of the β-lactamases. A total of 325 samples were collected from eight animal species. Of these, 34 bacterial isolates were identified as E. coli. The antibiotic resistance profile of the E. coli strains was as follows: 100% resistant to amoxicillin, aztreonam, and cephalosporins; 58.8% resistant to nalidixic acid, ciprofloxacin, and trimethoprim/sulfamethoxazole; 41.2% resistant to gentamicin and tobramycin; 11.8% resistant and 32.4% intermediate to cefoxitin; 97.1% sensible and 2.9% intermediate to amoxicillin/clavulanate; and 100% sensible to ertapenem, minocycline, imipenem, meropenem, amikacin, nitrofurantoin, fosfomycin, and colistin. All 34 E. coli strains met criteria for ESBL production. In total, 46 β-lactamase genes were detected: 43.5% blaTEM, 30.4% blaCTX-M (23.9% blaCTX-M-1 and 6.5% blaCTX-M-9), and 26.1% blaSHV (17.4% blaSHV-5 and 8.7% blaSHV-12). All the β-lactamases were found in dogs except for four blaSHV found in falcons. No plasmidic AmpC genes were found. The high prevalence of ESBL-producing E. coli strains in animals could become a zoonotic transmission vector

Transcriptomic and genetic associations between Alzheimer’s disease, Parkinson’s disease, and cancer

Alzheimer’s (AD) and Parkinson’s diseases (PD) are the two most prevalent neurodegenerative disorders in human populations. Epidemiological studies have shown that patients suffering from either condition present a reduced overall risk of cancer than controls (i.e., inverse comorbidity), suggesting that neurodegeneration provides a protective effect against cancer. Reduced risks of several site-specific tumors, including colorectal, lung, and prostate cancers, have also been observed in AD and PD. By contrast, an increased risk of melanoma has been described in PD patients (i.e., direct comorbidity). Therefore, a fundamental question to address is whether these associations are due to shared genetic and molecular factors or are explained by other phenomena, such as flaws in epidemiological studies, exposure to shared risk factors, or the effect of medications. To this end, we first evaluated the transcriptomes of AD and PD post-mortem brain tissues derived from the hippocampus and the substantia nigra and analyzed their similarities to those of a large panel of 22 site-specific cancers, which were obtained through differential gene expression meta-analyses of array-based studies available in public repositories. Genes and pathways that were deregulated in both disorders in each analyzed pair were examined. Second, we assessed potential genetic links between AD, PD, and the selected cancers by establishing interactome-based overlaps of genes previously linked to each disorder. Then, their genetic correlations were computed using cross-trait LD score regression and GWAS summary statistics data. Finally, the potential role of medications in the reported comorbidities was assessed by comparing disease-specific differential gene expression profiles to an extensive collection of differential gene expression signatures generated by exposing cell lines to drugs indicated for AD, PD, and cancer treatment (LINCS L1000). We identified significant inverse associations of transcriptomic deregulation between AD hippocampal tissues and breast, lung, liver, and prostate cancers, and between PD substantia nigra tissues and breast, lung, and prostate cancers. Moreover, significant direct (same direction) associations of deregulation were observed between AD and PD and brain and thyroid cancers, as well as between PD and kidney cancer. Several biological processes, including the immune system, oxidative phosphorylation, PI3K/AKT/mTOR signaling, and the cell cycle, were found to be deregulated in both cancer and neurodegenerative disorders. Significant genetic correlations were found between PD and melanoma and prostate cancers. Several drugs indicated for the treatment of neurodegenerative disorders and cancer, such as galantamine, selegiline, exemestane, and estradiol, were identified as potential modulators of the comorbidities observed between neurodegeneration and cancer.The research was supported by grant number PROMETEOII/2015/021 from Generalitat Valenciana and the national grant PI17/00719 from ISCIII-FEDER.Peer Reviewed"Article signat per 11 autors/es: Jaume Forés-Martos, Cesar Boullosa, David Rodrigo-Domínguez, Jon Sánchez-Valle, Beatriz Suay-García, Joan Climent, Antonio Falcó, Alfonso Valencia, Joan Anton Puig-Butillé, Susana Puig and Rafael Tabarés-Seisdedos"Postprint (published version

Synthesis of Quinolones and Zwitterionic Quinolonate Derivatives with Broad-Spectrum Antibiotic Activity

Quinolones are one of the most extensively used therapeutic families of antibiotics. However, the increase in antibiotic-resistant bacteria has rendered many of the available compounds useless. After applying our prediction model of activity against E. coli to a library of 1000 quinolones, two quinolones were selected to be synthesized. Additionally, a series of zwitterionic quinolonates were also synthesized. Quinolones and zwitterionic quinolonates were obtained by coupling the corresponding amine with reagent 1 in acetonitrile. Antibacterial activity was assessed using a microdilution method. All the compounds presented antibacterial activity, especially quinolones 2 and 3, selected by the prediction model, which had broad-spectrum activity. Furthermore, a new type of zwitterionic quinolonate with antibacterial activity was found. These compounds can lead to a new line of antimicrobials, as the structures, and, therefore, their properties, are easily adjustable in the amine in position 4 of the pyridine ring