Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis.

Copper-only superoxide dismutases (SODs) represent a new class of SOD enzymes that are exclusively extracellular and unique to fungi and oomycetes. These SODs are essential for virulence of fungal pathogens in pulmonary and disseminated infections, and we show here an additional role for copper-only SODs in promoting survival of fungal biofilms. The opportunistic fungal pathogen Candida albicans expresses three copper-only SODs, and deletion of one of them, SOD5, eradicated candidal biofilms on venous catheters in a rodent model. Fungal copper-only SODs harbor an irregular active site that, unlike their Cu,Zn-SOD counterparts, contains a copper co-factor unusually open to solvent and lacks zinc for stabilizing copper binding, making fungal copper-only SODs highly vulnerable to metal chelators. We found that unlike mammalian Cu,Zn-SOD1, C. albicans SOD5 indeed rapidly loses its copper to metal chelators such as EDTA, and binding constants for Cu(II) predict that copper-only SOD5 has a much lower affinity for copper than does Cu,Zn-SOD1. We screened compounds with a variety of indications and identified several metal-binding compounds, including the ionophore pyrithione zinc (PZ), that effectively inhibit C. albicans SOD5 but not mammalian Cu,Zn-SOD1. We observed that PZ both acts as an ionophore that promotes uptake of toxic metals and inhibits copper-only SODs. The pros and cons of a vulnerable active site for copper-only SODs and the possible exploitation of this vulnerability in antifungal drug design are discussed.

Infecciones por enterobacterias productoras de carbapenemasas en un servicio de urología. Un nuevo desafío / Infections by carbapenemase-producing enterobacteriaceae in a department of urology. A new challenge

Objetivos: Analizar las infecciones por enterobacterias productoras de carbapenemasas (EPC) y describir características y posibles factores de riesgo asociados con los pacientes de un servicio de urología. Material y métodos: Estudio observacional y retrospectivo. El criterio de inclusión fue haber estado ingresado en nuestro servicio de urología entre agosto de 2013 y diciembre de 2016. Se analizaron aquellos que presentaron positividad para EPC en al menos un cultivo. Se revisaron características basales y factores de riesgo. Asimismo se revisaron variables como presencia de infecciones urinarias previas, reingresos posteriores, el microorganismo, tipo de EPC, tratamiento administrado, un origen hospitalario o comunitario y la mortalidad. Resultados: De los 5.657 pacientes que cumplían criterio de inclusión, en 12 casos se aisló una EPC. Las infecciones por EPC representaron un 3,6% del total de infecciones relacionadas con la asistencia sanitaria y un 9,7% de las producidas por enterobacterias. Los factores analizados asociados a infección por EPC en nuestra serie son: presencia de catéteres urinarios (100%), haber sido sometido a tratamiento quirúrgico (58,3%), ingreso previo en UCI (8,3%) e inmunosupresión (16,6%). Con relación a la mortalidad, un 8,3% de los pacientes que presentaron infección por EPC fallecieron durante el ingreso. Conclusiones: Aproximadamente un 10% de las enterobacterias presenta patrón de resistencia a carbapenemasas en el paciente urológico de nuestro medio. Ser portador de catéter urinario y/o someterse a una cirugía son factores de riesgo asociados al desarrollo de estas infecciones en el paciente urológico de nuestro medio. La infección por una EPC eleva la morbimortalidad

Objectives: To analyse infections by carbapenemase-producing enterobacteriaceae (CPE) and describe the characteristics and potential risk factors associated with patients of a department of urology. Material and methods: Observational and retrospective study. The inclusion criterion was hospitalisation in our department of Urology between August 2013 and December 2016. We analysed those patients who were positive for CPE in at least 1 culture. We reviewed their baseline characteristics, risk factors and variables such as the presence of previous urinary tract infections, subsequent readmissions, the microorganism, type of CPE, treatment, origin (hospital or community) and mortality. Results: Of the 5,657 patients who met the inclusion criterion, a CPE was isolated in 12 cases. CPE infections represented 3.6% of all healthcare-associated infections and 9.7% of those caused by enterobacteria. The analysed factors associated with CPE infection in our series were the presence of urinary catheters (100%), undergoing surgery (58.3%), previous ICU admission (8.3%) and immunosuppression (16.6%). In terms of mortality, 8.3% of the patients who presented CPE infection died during hospitalisation. Conclusions: Approximately 10% of enterobacteria present a carbapenemase-resistance pattern in urological patients in our setting. Carrying a urinary catheter and/or undergoing surgery are risk factors associated with the development of these infections in urological patients in our setting. CPE infections increase morbidity and mortality