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Microbiol Spectr ; 10(1): e0108021, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1673361


The spread of carbapenem-resistant Pseudomonas aeruginosa and carbapenemase-producing Enterobacterales (CPE) has dramatically impacted morbidity and mortality. COVID-19 pandemic has favored the selection of these microorganisms because of the excessive and prolonged use of broad-spectrum antibiotics and the outbreaks related to patient transfer between hospitals and inadequate personal protective equipment. Therefore, early CPE detection is considered essential for their control. We aimed to compare conventional phenotypic synergy tests and two lateral flow immunoassays for detecting carbapenemases in Enterobacterales and P. aeruginosa. We analyzed 100 carbapenem-resistant Gram-negative bacilli isolates, 80 Enterobacterales, and 20 P. aeruginosa (86 isolates producing KPC, NDM, OXA-48, IMP, and VIM carbapenemases and 14 non-carbapenemase-producing isolates). We performed a modified Hodge test, boronic acid and ethylenediaminetetraacetic acid (EDTA) synergy tests, and two lateral flow immunoassays: RESIST-4 O.K.N.V. (Coris Bioconcept) and NG Test Carba 5 (NG Biotech). In total, 76 KPC, seven VIM, one NDM, one OXA-48, and one isolate coproducing KPC + NDM enzymes were included. The concordance of different methods estimated by the Kappa index was 0.432 (standard error: 0.117), thus showing a high variability with the synergy tests with boronic acid and EDTA and reporting 16 false negatives that were detected by the two immunochromatographic methods. Co-production was only detected using immunoassays. Conventional phenotypic synergy tests with boronic acid and EDTA for detecting carbapenemases are suboptimal, and their routine use should be reconsidered. These tests depend on the degree of enzyme expression and the distance between disks. Lateral flow immunoassay tests are a rapid and cost-effective tool to detect and differentiate carbapenemases, improving clinical outcomes through targeted therapy and promoting infection prevention measures. IMPORTANCE Infections due to multidrug-resistant pathogens are a growing problem worldwide. The production of carbapenemases in Pseudomonas aeruginosa and Enterobacterales cause a high impact on the mortality of infected patients. Therefore, it is of great importance to have methods that allow the early detection of these multi-resistant microorganisms, achieving the confirmation of the type of carbapenemase present, with high sensitivity and specificity, with the aim of improving epidemiological control, dissemination, the clinical course to through targeted antibiotic therapy and promoting infection control in hospitals.

Gammaproteobacteria/enzymology , Immunoassay/methods , Pseudomonas aeruginosa/enzymology , Carbapenems/metabolism , Carbapenems/pharmacology , Carbon-Nitrogen Ligases/metabolism , Drug Resistance , Immunoassay/standards , Phenotype , Pseudomonas aeruginosa/drug effects
Science ; 372(6547): 1169-1175, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1583231


Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.

Anti-Bacterial Agents/pharmacology , Cystathionine gamma-Lyase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hydrogen Sulfide/metabolism , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Biofilms , Crystallography, X-Ray , Cystathionine gamma-Lyase/chemistry , Cystathionine gamma-Lyase/genetics , Cystathionine gamma-Lyase/metabolism , Drug Discovery , Drug Resistance, Bacterial , Drug Synergism , Drug Tolerance , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/enzymology , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/growth & development , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/enzymology , Staphylococcus aureus/genetics , Staphylococcus aureus/growth & development