Trimethoprim, failure to penetrate into<i>Pseudomonas aeruginosa</i>cells

Werner, Rolf G.; Goeth, H

doi:10.1111/j.1574-6968.1984.tb01063.x

Cited by 5 publications

(2 citation statements)

References 7 publications

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“…Regardless of peptide valency, WD40 MICs were reduced 2-fold when combined in a physical mixture with free linezolid in microdilution assays with PA14, indicating linezolid uptake (Figure B). This was also true with trimethoprim, another antibiotic with poor membrane penetration that targets the bacterial folate pathway . In contrast, WD10 MICs were not consistently reduced when combined with free antibiotics, suggesting weaker membrane disruption.…”

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confidence: 90%

“…This was also true with trimethoprim, another antibiotic with poor membrane penetration that targets the bacterial folate pathway. 21 In contrast, WD10 MICs were not consistently reduced when combined with free antibiotics, suggesting weaker membrane disruption. From the potentiator panel, we subsequently focused on WD10 with 7 peptides and WD40 with 5 peptides (i.e., the candidates with the fewest peptides) because higher-valency potentiator candidates precipitated during microdilution assays.…”

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confidence: 98%

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Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization

et al. 2021

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The drug-impermeable bacterial membrane in Gram-negative pathogens limits antibiotic access to intracellular drug targets. To expand our rapidly waning antibiotic arsenal, one approach is to improve the intracellular delivery of drugs with historically poor accumulation in Gram-negative bacteria. To do so, we engineered macromolecular potentiators to permeabilize the Gram-negative membrane to facilitate drug influx. Potentiators, known as WD40, were synthesized by grafting multiple copies of a cationic α-helical antimicrobial peptide, WLBU2, onto a dextran polymer scaffold. WD40 enabled drug uptake in the model pathogen P. aeruginosa , a capability that was not observed with unmodified WLBU2 peptide. WD40 was able to reduce minimum inhibitory concentrations of a drug panel by up to 3 orders of magnitude. Hydrophobic and highly three-dimensional antibiotics exhibited the greatest potentiation. Antibiotic activity was potentiated in several clinical strains and resulted in sensitization of drug-resistant strains to rifampin, a drug not previously used for Gram-negative infections.

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Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization

et al. 2021

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Resistance to Trimethoprim

Elwell¹,

Fling²

1989

Handbook of Experimental Pharmacology

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Biophysical principles predict fitness landscapes of drug resistance

Rodrigues

Bershtein

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

265

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Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi. We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype–phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.

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Trimethoprim, failure to penetrate intoPseudomonas aeruginosacells

Cited by 5 publications

References 7 publications

Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization

Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization

Resistance to Trimethoprim

Biophysical principles predict fitness landscapes of drug resistance

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