RESUMO
Non-small cell lung cancer (NSCLC) is a type of lung cancer associated with translocation of the EML4 and ALK genes on the short arm of chromosome 2. This leads to the development of an aberrant protein kinase with a deregulated catalytic domain, the cdALK+. Currently, different ALK inhibitors (iALKs) have been proposed to treat ALK+ NSCLC patients. However, the recent resistance to iALKs stimulates the exploration of new iALKs for NSCLC. Here, we describe an in silico approach to finding FDA-approved drugs that can be used by pharmacological repositioning as iALK. We used homology modelling to obtain a structural model of cdALK+ protein and then performed molecular docking and molecular dynamics of the complex cdALK+-iALKs to generate the pharmacophore model. The pharmacophore was used to identify potential iALKs from FDA-approved drugs library by ligand-based virtual screening. Four pharmacophores with different atomistic characteristics were generated, resulting in six drugs that satisfied the proposed atomistic positions and coupled at the ATP-binding site. Mitoxantrone, riboflavin and abacavir exhibit the best interaction energies with 228.29, 165.40 and 133.48 KJoul/mol respectively. In addition, the special literature proposed these drugs for other types of diseases due to pharmacological repositioning. This study proposes FDA-approved drugs with ALK inhibitory characteristics. Moreover, we identified pharmacophores sites that can be tested with other pharmacological libraries.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ciclopropanos , Didesoxiadenosina/análogos & derivados , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/genética , Mitoxantrona/uso terapêutico , Simulação de Acoplamento Molecular , Quinase do Linfoma Anaplásico/genética , Receptores Proteína Tirosina Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas de Fusão Oncogênica/genéticaRESUMO
Nursing homes are institutions with high prevalence of urinary tract infections caused by ESBL-producing E. coli with several virulence factors. The aim of this study was to determine the frequency of the bla CTX-M gene and eight virulence genes in 35 ESBL-producing uropathogenic E. coli from six nursing homes in Peru during 2018. Of the E. coli samples, 57.1% (20/35) were carriers of the bla CTX-M gene. Furthermore, we obtained frequencies of 46% (15/35) and 37% (13/35) for hly-alpha and cnf-1, respectively; we also found high presence of the iucC (63%, 22/35), aer (94%, 33/35) and chuA genes (94%, 33/34) as well as a frequency of 46% (16/35) and 91% (32/34) for the pap GII and nanA genes, respectively. The bla CTX-M gene is predominant and a high frequency of exotoxins gives it a competitive advantage for spreading into the bloodstream.
Los asilos de ancianos son instituciones con una alta prevalencia de infecciones del tracto urinario ocasionado por Escherichia coli productoras de ß-lactamasas de espectro extendido (BLEE), con diversos factores de virulencia. El objetivo del estudio fue determinar la frecuencia del gen bla CTX-M y de ocho genes de virulencia en 35 E. coli uropatógenas productoras de BLEE provenientes de seis asilos en Perú, durante el 2018. El 57,1% (20/35) de las E. coli fueron portadores del gen bla CTX-M. Además, se obtuvo una frecuencia del 46% (15/35) y 37% (13/35) de hly-alfa y cnf-1, respectivamente; elevada presencia de los genes iucC (63%, 22/35), aer (94%, 33/35) y chuA (94%, 33/34) y una frecuencia del 46% (16/35) y del 91% (32/34) de los genes pap GII y nanA, respectivamente. Existe predominancia en la distribución del gen bla CTX-M, además de una alta frecuencia de exotoxinas que le confieren una ventaja competitiva para diseminarse hacia el torrente sanguíneo.
Assuntos
Infecções por Escherichia coli , Escherichia coli Uropatogênica , Infecções por Escherichia coli/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Casas de Saúde , Peru/epidemiologia , Escherichia coli Uropatogênica/genética , Fatores de Virulência/genética , beta-Lactamases/genéticaRESUMO
RESUMEN Los asilos de ancianos son instituciones con una alta prevalencia de infecciones del tracto urinario ocasionado por Escherichia coli productoras de ß-lactamasas de espectro extendido (BLEE), con diversos factores de virulencia. El objetivo del estudio fue determinar la frecuencia del gen bla CTX-M y de ocho genes de virulencia en 35 E. coli uropatógenas productoras de BLEE provenientes de seis asilos en Perú, durante el 2018. El 57,1% (20/35) de las E. coli fueron portadores del gen bla CTX-M. Además, se obtuvo una frecuencia del 46% (15/35) y 37% (13/35) de hly-alfa y cnf-1, respectivamente; elevada presencia de los genes iucC (63%, 22/35), aer (94%, 33/35) y chuA (94%, 33/34) y una frecuencia del 46% (16/35) y del 91% (32/34) de los genes pap GII y nanA, respectivamente. Existe predominancia en la distribución del gen bla CTX-M, además de una alta frecuencia de exotoxinas que le confieren una ventaja competitiva para diseminarse hacia el torrente sanguíneo.
ABSTRACT Nursing homes are institutions with high prevalence of urinary tract infections caused by ESBL-producing E. coli with several virulence factors. The aim of this study was to determine the frequency of the bla CTX-M gene and eight virulence genes in 35 ESBL-producing uropathogenic E. coli from six nursing homes in Peru during 2018. Of the E. coli samples, 57.1% (20/35) were carriers of the bla CTX-M gene. Furthermore, we obtained frequencies of 46% (15/35) and 37% (13/35) for hly-alpha and cnf-1, respectively; we also found high presence of the iucC (63%, 22/35), aer (94%, 33/35) and chuA genes (94%, 33/34) as well as a frequency of 46% (16/35) and 91% (32/34) for the pap GII and nanA genes, respectively. The bla CTX-M gene is predominant and a high frequency of exotoxins gives it a competitive advantage for spreading into the bloodstream.
Assuntos
Humanos , Masculino , Feminino , Idoso , Idoso de 80 Anos ou mais , Virulência , Escherichia coli , Escherichia coli Uropatogênica , Antibacterianos , Infecções Urinárias , Resistência beta-Lactâmica , Fatores de Virulência , Infecções por Enterobacteriaceae , Instituição de Longa Permanência para Idosos , InfecçõesRESUMO
Descriptive study in which 24 urine samples from older adults with urinary tract infection (UTI), from nursing homes, were evaluated; in order to identify differences in the immune and biochemical response from older adults with UTI by Escherichia coli (E. coli) to major virulence factors in the pathogenesis of UTI. Iron concentration, TNF-α, IL-1ß and antioxidant capacity in urine were determined. A relation was found between, an increase in iron and red blood cell concentration in urine, and the presence of the pap GII gene found in E. coli. It is concluded that older adults, with UTIs by E. coli with the gene pap GII, have increased tissue damage.
Con el objetivo de evidenciar diferencias en la respuesta inmunológica y bioquímica de ancianos con infección del tracto urinario (ITU) por Escherichia coli (E. coli) frente a factores de virulencia de importancia en la patogenia de la ITU, se realizó un estudio descriptivo en el cual se evaluaron 24 muestras de orina de adultos mayores con ITU provenientes de centros de reposo gerontológicos. Se determinó la concentración de hierro, TNF-α, IL-1ß y la capacidad antioxidante en la orina, encontrándose una relación entre una mayor concentración de hierro y de hematíes en la orina con la presencia del gen pap GII en la E. coli. Se concluye que los adultos mayores con ITU por E. coli portadoras del gen pap GII, presentan mayor daño tisular.
Assuntos
Infecções por Escherichia coli , Infecções Urinárias , Escherichia coli Uropatogênica , Idoso , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Humanos , Imunidade , Infecções Urinárias/imunologia , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/genética , Escherichia coli Uropatogênica/patogenicidade , Fatores de VirulênciaRESUMO
RESUMEN Con el objetivo de evidenciar diferencias en la respuesta inmunológica y bioquímica de ancianos con infección del tracto urinario (ITU) por Escherichia coli (E. coli) frente a factores de virulencia de importancia en la patogenia de la ITU, se realizó un estudio descriptivo en el cual se evaluaron 24 muestras de orina de adultos mayores con ITU provenientes de centros de reposo gerontológicos. Se determinó la concentración de hierro, TNF-α, IL-1β y la capacidad antioxidante en la orina, encontrándose una relación entre una mayor concentración de hierro y de hematíes en la orina con la presencia del gen pap GII en la E. coli. Se concluye que los adultos mayores con ITU por E. coli portadoras del gen pap GII, presentan mayor daño tisular.
ABSTRACT Descriptive study in which 24 urine samples from older adults with urinary tract infection (UTI), from nursing homes, were evaluated; in order to identify differences in the immune and biochemical response from older adults with UTI by Escherichia coli (E. coli) to major virulence factors in the pathogenesis of UTI. Iron concentration, TNF-α, IL-1β and antioxidant capacity in urine were determined. A relation was found between, an increase in iron and red blood cell concentration in urine, and the presence of the pap GII gene found in E. coli. It is concluded that older adults, with UTIs by E. coli with the gene pap GII, have increased tissue damage.
