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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES A pathological condition with a high level of severity, caused by drug resistance, is one of the major public health problems worldwide and has worrying consequences. This scenario becomes more complex when we mention the infections caused by the pathogens ESKAPE - Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. - (because they are microorganisms with high multiresistance and virulence). Thus, repositioning has been a trending topic in the literature and consists of finding new uses for drugs approved for clinical use. In this sense, the present study aimed, in the published articles, to present to the scientific community the current research on treatment alternatives for infections caused by ESKAPE pathogens and perspectives on the anti-infective activities of proton pump inhibitors (PPIs). In the manuscripts, the biological activities of the benzodiazepines clonazepam and diazepam and PPIs omeprazole and esomeprazole as candidate drugs for redirection were verified. Scientific database searches were carried out on treatment alternatives for ESKAPE pathogens and anti-infective activities of PPIs. In addition, the in vitro antibacterial activities of clonazepam, diazepam, omeprazole and esomeprazole against American Type Culture Collection (ATCC) standard bacterial strains and clinical isolates of ESKAPE pathogens were analyzed, determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), its interactions with the standard antibacterial ciprofloxacin by the checkerboard method and determination of the fractional inhibitory concentration index (FICI). For clonazepam and diazepam, the clinical impact of the use of these drugs in repositioning was analyzed, and for omeprazole and esomeprazole, the ability to cleave plasmid DNA was verified, and molecules capable of cleavage can act as antibacterials. In the treatment alternatives for infections caused by ESKAPE pathogens, drugs from the pharmacological classes of antineoplastic, anti-inflammatory, antidepressant and antialcoholic have been reported. In the study covering the anti-infective activities of PPIs, activities of these drugs against 17 infectious agents were described, some of them Pseudomonas aeruginosa, Mycobacterium tuberculosis, Enterococcus faecalis, Staphylococcus aureus, Candida albicans and SARS-CoV-2. In antibacterial activity assays, the combination of clonazepam and diazepam with ciprofloxacin was synergistic against 10 strains and five strains of ESKAPE pathogens (FICI

The persistent use of antibiotics, self-medication and exposure to hospital infections has led to an increase in multidrug-resistant microorganisms. With this emergence of bacterial multiresistance, six pathogens play an essential role. The term ESKAPE deals with six microorganisms with high multiresistance and virulence: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. The World Health Organization (WHO) recently released a list of priority pathogens for research and development of new antibacterial agents. All ESKAPE pathogens are on this list. Thus, listing a big question: the emerging importance of new treatment strategies for infections caused by these microorganisms. O persistente uso de antibióticos, automedicação e exposição a infecções hospitalares têm provocado o aumento de microrganismos multirresistentes. Com essa emergência da multirresistência bacteriana, seis patógenos figuram papel essencial. O termo ESKAPE trata de seis microrganismos com alta multirresistência e virulência: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa e Enterobacter spp. Recentemente, a Organização Mundial da Saúde (OMS) liberou uma lista de agentes patogênicos prioritários para pesquisa e desenvolvimento de novos agentes antibacterianos. Todos os patógenos ESKAPE fazem parte desta lista. Elencando, assim, uma grande questão: a importância emergente de novas estratégias de tratamento para infecções ocasionadas por esses microrganismos.

OBJECTIVE: The objective of this work was to evaluate the prevalence and resistance profile of microorganisms isolated from skin and soft tissue secretions. This type of study, as far as we know, was the first carried out in this hospital with a period of four years and a large number of samples. METHODS: A retrospective observational study of cultures of skin infections collected in a tertiary teaching hospital was carried out from January 2014 to December 2017. The tests for identification of the microorganisms and sensitivity profile were carried out using systems conventional and automated systems (Vitek® 2 - bioMérieux). RESULTS: During the period of this study, 675 samples were positive, being Staphylococcus aureus (118; 17.48%), Pseudomonas aeruginosa (106; 15.70%), Staphylococcus epidermidis (65; 9,63%) and Escherichia coli (60%) were positive in the study period (60; 8.89%) the predominant microorganisms. Regarding Pseudomonas aeruginosa, 53.77% of the strains had resistance to imipenem and 44.34% to meropenem. Therapeutic options for the treatment of infections caused by this microorganism are limited. CONCLUSION: The epidemiological profile of the agents involved is similar to that reported in the international literature, which differentiates the sensitivity profile. A fact that needs monitoring is that Pseudomonas aeruginosa occupied the second place in the etiology and presented significant resistance against the carbapenems. OBJETIVO: O objetivo deste trabalho foi avaliar a prevalência e perfil de resistência dos microrganismos isolados de secreções de pele e tecidos moles. Este tipo de estudo, pelo que é de nosso conhecimento, foi o primeiro realizado neste hospital com período de quatro anos e elevado número de amostras. MÉTODOS: Realizou-se um estudo observacional retrospectivo de culturas de infecções de pele coletadas em hospital escola terciário, no período de janeiro de 2014 a dezembro de 2017. Os testes de identificação dos microrganismos e perfil de sensibilidade foram efetuados por meio de sistemas convencionais e automatizados (Vitek® 2 – bioMérieux). RESULTADOS: No período deste estudo, 675 amostras resultaram positivas, sendo Staphylococcus aureus (118; 17,48%), Pseudomonas aeruginosa (106; 15,70%), Staphylococcus epidermidis (65; 9,63%) e Escherichia coli (60; 8,89%) os microrganismos predominantes. Em relação à Pseudomonas aeruginosa, 53,77% das cepas apresentaram resistência ao imipenem e 44,34% ao meropenem. As opções terapêuticas para o tratamento das infecções causadas por esse microrganismo são limitadas. CONCLUSÕES: O perfil epidemiológico dos agentes envolvidos é similar ao citado na literatura internacional, o que diferencia é o perfil de sensibilidade. Fato que necessita monitoramento é que Pseudomonas aeruginosa ocupou o segundo lugar na etiologia e apresentou significativa resistência frente aos carbapenêmicos.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES The emergence of multiresistance to commercially available antimicrobials today is likely to continue to be one of the major global public health problems, as it has worrying clinical and economic consequences. Concomitant with the increase in infections caused by multidrugresistant microorganisms (MDR), there has been a drastic reduction of new antibacterials in the market, as well as investments for their creation. In addition to antimicrobial resistance, resistance to antitumor drugs is already a reality. Thus, it is essential to search for new substances and / or compounds that exhibit antibacterial and / or antitumor activity. With this, drug repositioning has emerged as an alternative approach for the faster identification of effective drugs. In this sense, the present study aimed, in the first article, to present to the scientific community the current research on the repositioning of antidepressants for the treatment of infections caused by microorganisms. In the second manuscript, the individual antibacterial activity and in combination with antibacterials of the non-antibiotics escitalopram oxalate and clonazepam were analyzed against standard strains and clinical isolates multiresistant. In addition, the chemical nuclease ability of these drugs was analyzed. In the first article, we report that antidepressant drugs, highlighting the class of selective serotonin reuptake inhibitors (SSRIs), have significant activity against several microorganisms. We present 14 studies covering the repositioning of antidepressant drugs to treat infections. Among the antidepressants, escitalopram oxalate was reported with activity reported in vitro against standard bacterial strains. In the second manuscript, we report the antibacterial and chemical nuclease activity of the drugs oxalate of escitalopram and clonazepam. The first was active against a standard Gram-negative strain and eight Grampositive MDR clinical isolates. The second drug showed activity against both Gram-positive and Gram-negative, with four standard Gram-positive strains and all Gram-positive and Gram-negative MDR clinical isolates. Escitalopram oxalate and clonazepam showed activity in vitro when individually associated with ciprofloxacin and sulfamethoxazole-trimethoprim against standard strains and clinical MDR Gram-positive isolates. Clonazepam was also active against a gram-negative bacterium. Clonazepam was able to cleave the plasmidial DNA. Further studies should be performed by our research group, in order to verify the activity of clonazepam against tumor cell lines. Therefore, in this work we show that these two drugs constitute a promising alternative to redirection in the treatment of infectious diseases and also for neoplasias. Further studies, using different techniques, are needed to elucidate the mechanisms of action involved. A emergência da multirresistência aos antimicrobianos disponíveis comercialmente na atualidade é provavelmente e continuará a ser um dos grandes problemas de saúde pública mundial, dado que apresenta consequências clínicas e econômicas preocupantes. Concomitante ao aumento das infecções ocasionadas por microrganismos resistentes a múltiplas drogas (MDR) ocorreu uma redução drástica de novos antibacterianos no mercado, bem como, investimentos para sua criação. Além da resistência aos antimicrobianos, a resistência aos medicamentos antitumorais também já é uma realidade. Assim, é essencial a pesquisa de novas substâncias e/ou compostos que apresentem atividade antibacteriana e/ou antitumoral. Com isso, o reposicionamento de fármacos surgiu como uma abordagem alternativa para a identificação mais rápida de medicamentos eficazes. Nesse sentido, o presente estudo objetivou, no primeiro artigo, apresentar à comunidade científica a pesquisa atual do reposicionamento de antidepressivos para o tratamento de infecções ocasionadas por microrganismos. No segundo manuscrito, analisou-se a atividade antibacteriana individual e em combinação com antibacterianos dos não-antibióticos oxalato de escitalopram e clonazepam frente a cepas padrão e isolados clínicos multirresistentes. Além disso, foi analisada a capacidade de nuclease química desses medicamentos. No primeiro artigo, relatamos que medicamentos antidepressivos, destacando a classe dos inibidores seletivos da recaptação da serotonina (ISRSs), apresentam atividade significativa contra vários microrganismos. Foram apresentados 14 estudos abrangendo o reposicionamento de medicamentos antidepressivos para tratamento de infecções. Dentre os antidepressivos, foi citado o oxalato de escitalopram com atividade relatada in vitro frente a cepas bacterianas padrão. No segundo manuscrito, relatamos a atividade antibacteriana e de nuclease química dos medicamentos oxalato de escitalopram e clonazepam. O primeiro foi ativo frente a uma cepa padrão Gram-negativa e oito isolados clínicos MDR Gram-positivos. O segundo medicamento apresentou atividade tanto frente a Gram-positivas quanto a Gram-negativas, sendo quatro cepas padrão Gram-positivas e todos os isolados clínicos MDR Gram-positivos e Gram-negativos. Oxalato de escitalopram e clonazepam apresentaram atividade in vitro quando associados, individualmente, com ciprofloxacino e sulfametoxazol-trimetoprima frente a cepas-padrão e isolados clínicos MDR Gram-positivos. O clonazepam também foi ativo frente a uma bactéria Gram-negativa. Clonazepam foi capaz de clivar o DNA plasmidial. Mais estudos devem ser realizados pelo nosso grupo de pesquisa, com objetivo de verificar a atividade do clonazepam frente a linhagens celulares tumorais. Portanto, nesse trabalho evidenciamos que estes dois medicamentos constituem uma alternativa promissora ao redirecionamento no tratamento de doenças infecciosas e também para neoplasias. São necessários estudos adicionais, utilizando diferentes técnicas, para a elucidação dos mecanismos de ação envolvidos.