The structure of Acinetobacter-secreted protease CpaA complexed with its chaperone CpaB reveals a novel mode of a T2SS chaperone-substrate interaction Protein Structure and Folding

Members of the Acinetobacter baumannii-calcoaceticus complex are nosocomial pathogens frequently causing multidrug-resistant infections that are increasing at alarming rates. A. baumannii has become the Gram-negative bacterium with the highest rate of multidrug resistance. As such, it is categorized by the World Health Organization as a critical priority for the research and development of new antimicrobial therapies. The zinc-dependent metalloendopeptidase CpaA is a predominant substrate of the type II secretion system (T2SS). CpaA is also a virulence factor of medically relevant Acinetobacter strains that specifically degrade the human glycoprotein coagulation factor XII and not its deglycosylated form, but the mechanism for this specificity is unknown. CpaB is a membrane-anchored T2SS chaperone that interacts with CpaA and is required for its stability and secretion. Here, we report the crystal structure of the CpaAB complex at 2.6-Å resolution, revealing four glycan-binding domains in CpaA that were not predicted from its primary sequence and may explain CpaA's glycoprotein-targeting activity. The structure of the complex identified a novel mode for chaperone–protease interactions in which the protease surrounds the chaperone. The CpaAB organization was akin to zymogen inactivation, with CpaB serving as a prodomain that inhibits catalytically active CpaA. CpaB contains a C-terminal tail that appears to block access to the CpaA catalytic site, and functional ex...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Microbiology Source Type: research

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The lack of therapeutic options to treat infections caused by recalcitrant multidrug-resistant pathogens, especially Gram-negative bacteria, is apparent. Therefore, it is imperative to develop new strategies to address the problem of antimicrobial resistance. Repurposing non-antibiotic commercial drugs for antimicrobial therapy presents a viable option. We screened six anticancer drugs for their potential use in antimicrobial therapy. Here, we provide in vitro evidence that suggests feasibility to repurpose the anticancer drug mitomycin C against multidrug-resistant Gram-negative bacteria. We also demonstrated that mitomyc...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
Authors: Goret NE, Goret CC, Ozkan OF Abstract Necrotizing fasciitis (NF) is a rare, life-threatening soft tissue infection that affects the skin, subcutaneous tissue, fascia, and muscle, and is characterized by rapid spread and invasion of pathogens. Treatment is possible with early diagnosis, appropriate antibiotic therapy, and quick surgical intervention. Nevertheless, despite all interventions, it is sometimes difficult to manage NF. The Authors present the case of a patient with extensive NF caused by multidrug-resistant Acinetobacter baumannii (A. baumannii) that developed following an intramuscular injection...
Source: Annali Italiani di Chirurgia - Category: Surgery Tags: Ann Ital Chir Source Type: research
Conclusion: New carbapenem/βLI combinations may be viable alternatives to antimicrobial combination therapy as they displayed high efficacy in vitro and in vivo. Meropenem/Avibactam and Meropenem/Relebactam should be tested on larger sample sizes with different carbapenemases before progressing further in its preclinical development. Introduction Carbapenem resistant Gram-negative bacteria have been gradually increasing in prevalence in recent years. In the United States, the latest CDC Antibiotic Resistance Threat Report indicates that Carbapenem-Resistant Enterobacteriaceae (CREs) are responsible for 9,000 a...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
Application of Antimicrobial Peptides of the Innate Immune System in Combination With Conventional Antibiotics—A Novel Way to Combat Antibiotic Resistance? Maria S. Zharkova1, Dmitriy S. Orlov1, Olga Yu. Golubeva2, Oleg B. Chakchir3, Igor E. Eliseev3, Tatyana M. Grinchuk4 and Olga V. Shamova1* 1Laboratory of Design and Synthesis of Biologically Active Peptides, Department of General Pathology and Pathophysiology, FSBSI Institute of Experimental Medicine, Saint Petersburg, Russia 2Laboratory of Nanostructures Research, Institute of Silicate Chemistry of the Russian Academy of Sciences, Saint Petersburg, Russia ...
Source: Frontiers in cellular and infection microbiology - Category: Microbiology Source Type: research
Conclusion The results of our study demonstrate that robenidine is not suitable as a sole antimicrobial agent for the treatment of Gram-negative pathogen infections due to the lack of activity against the majority of Gram-negative isolates except for A. baumannii and A. calcoaceticus. However, we demonstrated in vitro efficacy against all selected Gram-negative organisms when robenidine was tested in combination with EDTA or PMBN, including against multidrug-resistant strains. Therefore, robenidine may be an appropriate candidate as a component of a combination preparation for the treatment of otitis externa in dogs. This...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
ConclusionThese findings might effectively help to avert the severe complications of diabetic foot infections (DFIs) besides our endeavors to find new antimicrobial wound dressings.
Source: Diabetes and Metabolic Syndrome: Clinical Research and Reviews - Category: Endocrinology Source Type: research
Abstract Background and objective: Bacterial multidrug resistance is particularly common in Gram-negative bacilli (GNB), with important clinical consequences regarding their spread and treatment options. The aim of this study was to investigate the trend of multidrug-resistant GNB (MDR-GNB) in high-risk hospital departments, between 2000⁻2015, in intervals of five years, with the intention of improving antibiotic therapy policies and optimising preventive and control practices. Materials and methods: This is an observational, retrospective study performed in three departments of the most important tertiary healt...
Source: Medicina (Kaunas) - Category: Universities & Medical Training Authors: Tags: Medicina (Kaunas) Source Type: research
Introduction - Acinetobacter baumannii is a Gram-negative strictly aerobic non-fermentative coccobacillus, widely distributed in nature. Multidrug resistant strains, including carbapenem antibiotic resistant, have been associated with fulminant severe sepsis and high overall mortality rate, ranging between 25 and 54%. This is true mainly for intensive care unit (ICU) and immunocompromised patients. Although CRAB bacteremia has previously been reported, studies involving hemato-oncological patients have rarely been reported.Aim - To investigate factors associated with 7 day mortality, defined as death within 7 days of docum...
Source: Blood - Category: Hematology Authors: Tags: 203. Lymphocytes, Lymphocyte Activation, and Immunodeficiency, including HIV and Other Infections Source Type: research
ConclusionCommunity-acquired bacteremia caused by A. baumannii was rare but associated with a severe outcome. Further investigation of potential virulence factors of community-acquired A. baumannii is required.
Source: Journal of Microbiology, Immunology and Infection - Category: Microbiology Source Type: research
Purpose of review Describe the risk factors and discuss the management of multidrug-resistant (MDR) bacteria responsible for pneumonia among critically ill patients, including methicillin-resistant Staphylococcus aureus, extended spectrum beta-lactamase-producing Enterobactericeae, carbapenem-resistant Enterobactericeae, multidrug resistant Pseudomonas aeruginosa, and Acinetobacter baumannii. Recent findings Multiple factors have been associated with infections because of MDR bacteria, including prolonged hospital stay, presence of invasive devices, mechanical ventilation, colonization with resistant pathogens, and us...
Source: Current Opinion in Critical Care - Category: Nursing Tags: INFECTIOUS DISEASES: Edited by Antoni Torres Source Type: research
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