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Potent LpxC Inhibitors with In Vitro Activity against Multidrug-Resistant Pseudomonas aeruginosa.

ABSTRACT: New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against Pseudomonas aeruginosa We report here the in vitro antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in phase 1 clinical trials. In addition, we describe the profiles of three additional LpxC inhibitors that were identified as potential lead molecules. These efforts did not produce an additional development candidate with a sufficiently large therapeutic window and the program was subsequently terminated.

SUBMITTER: Krause KM

PROVIDER: S-EPMC6811409 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Potent LpxC Inhibitors with In Vitro Activity against Multidrug-Resistant Pseudomonas aeruginosa.

Krause Kevin M KM Haglund Cat M CM Hebner Christy C Serio Alisa W AW Lee Grace G Nieto Vincent V Cohen Frederick F Kane Timothy R TR Machajewski Timothy D TD Hildebrandt Darrin D Pillar Chris C Thwaites Mary M Hall Danielle D Miesel Lynn L Hackel Meredith M Burek Amanda A Andrews Logan D LD Armstrong Eliana E Swem Lee L Jubb Adrian A Cirz Ryan T RT

Antimicrobial agents and chemotherapy 20191022 11

New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against Pseudomonas aeruginosa We report here the in vitro antibacterial activity and pharmacodynamics of ACHN-975, ...[more]

PMID: 31451507

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Project description:ObjectiveDrawing a growth curve of multidrug-resistant Pseudomonas aeruginosa (MDR-PA) provides a foundation for susceptibility testing. By observing in vitro antibacterial activity and ultrastructure cthanges on MDR-PA of the effective components in the drug-containing serum of rats after the administration of Fuzheng Jiedu Huayu decoction (FJHD), we evaluated the inhibition and direct destruction effect of bacteria by TCM alone or combined with antibiotics.MethodsThe absorbance values of MDR-PA were determined at different detection time points, and a growth curve was drawn. After gavage with FJHD, drug-containing serum was collected from the rats. Using Imipenem/cilastatin sodium as the positive drug control, the in vitro antibacterial potency of FJHD and its drug-containing serum alone or in combination with antibiotics against MDR-PA was observed. The ultrastructural changes of MDR-PA treated by FJHD combined with antibiotics were observed by transmission electron microscopy.ResultsGrowth of the experimental strain manifested a lag phase in the first 1-4 h, an exponential growth phase at 5-20 h, and a plateau phase after 20 h. The best detection time during the susceptibility test was 16-20 h. The minimum inhibitory concentration (MIC) value of the FJHD extract group was 0.2 g/mL. The MIC value of the pure Imipenem/cilastatin sodium group was 16 μg/mL. The MIC values of Imipenem/cilastatin sodium + blank serum, 0.5-, 1-, and 2-fold drug-containing serum groups were all 16 μg/mL. The MIC values of Imipenem/cilastatin sodium + 4- and 8-fold drug-containing serum groups were both 8 μg/mL. By observation under a transmission electron microscope, Imipenem/cilastatin sodium + 0.5-, 1-, and 2-fold drug-containing serum groups showed bacterial structural damage. The degree of bacterial destruction was more obvious and the quantity of damaged bacteria was increased in the Imipenem/cilastatin sodium + 4- and 8-fold drug-containing serum groups.ConclusionDrawing the growth curve of the experimental strain had high application value for ensuring the accuracy of the drug sensitivity test results. TCM combined with antibiotics could enhance the antibacterial and direct destruction effect of bacteria in vitro, thereby inhibiting bacterial resistance to a certain extent.

Project description:BackgroundWe aimed to identify the main spreading clones, describe the resistance mechanisms associated with carbapenem- and/or multidrug-resistant P. aeruginosa and characterize patients at risk of acquiring these strains in Estonian hospitals.MethodsNinety-two non-duplicated carbapenem- and/or multidrug-resistant P. aeruginosa strains were collected between 27th March 2012 and 30th April 2013. Clinical data of the patients was obtained retrospectively from the medical charts. Clonal relationships of the strains were determined by whole genome sequencing and analyzed by multi-locus sequence typing. The presence of resistance genes and beta-lactamases and their origin was determined. Combined-disk method and PCR was used to evaluate carbapenemase and metallo-beta-lactamase production.ResultsForty-three strains were carbapenem-resistant, 11 were multidrug-resistant and 38 were both carbapenem- and multidrug-resistant. Most strains (54%) were isolated from respiratory secretions and caused an infection (74%). Over half of the patients (57%) were ≥ 65 years old and 85% had ≥1 co-morbidity; 96% had contacts with healthcare and/or had received antimicrobial treatment in the previous 90 days. Clinically relevant beta-lactamases (OXA-101, OXA-2 and GES-5) were found in 12% of strains, 27% of which were located in plasmids. No Ambler class B beta-lactamases were detected. Aminoglycoside modifying enzymes were found in 15% of the strains. OprD was defective in 13% of the strains (all with CR phenotype); carbapenem resistance triggering mutations (F170 L, W277X, S403P) were present in 29% of the strains. Ciprofloxacin resistance correlated well with mutations in topoisomerase genes gyrA (T83I, D87N) and parC (S87 L). Almost all strains (97%) with these mutations showed ciprofloxacin-resistant phenotype. Multi-locus sequence type analysis indicated high diversity at the strain level - 36 different sequence types being detected. Two sequence types (ST108 (n = 23) and ST260 (n = 18)) predominated. Whereas ST108 was associated with localized spread in one hospital and mostly carbapenem-resistant phenotype, ST260 strains occurred in all hospitals, mostly with multi-resistant phenotype and carried different resistance genotype/machinery.ConclusionsDiverse spread of local rather than international P. aeruginosa strains harboring multiple chromosomal mutations, but not plasmid-mediated Ambler class B beta-lactamases, were found in Estonian hospitals.Trial registrationThis trial was registered retrospectively in ClinicalTrials.gov ( NCT03343119 ).

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Potent LpxC Inhibitors with In Vitro Activity against Multidrug-Resistant Pseudomonas aeruginosa.

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Potent LpxC Inhibitors with <i>In Vitro</i> Activity against Multidrug-Resistant Pseudomonas aeruginosa.

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