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Wesseling CMJ, Slingerland CJ, Veraar S, et al. Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens. ACS Infect Dis. 2021;7(12):3314-3335doi: 10.1021/acsinfecdis.1c00466.
Wesseling, C. M. J., Slingerland, C. J., Veraar, S., Lok, S., & Martin, N. I. (2021). Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens. ACS infectious diseases, 7(12), 3314-3335. https://doi.org/10.1021/acsinfecdis.1c00466
Wesseling, Charlotte M J, et al. "Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens." ACS infectious diseases vol. 7,12 (2021): 3314-3335. doi: https://doi.org/10.1021/acsinfecdis.1c00466
Wesseling CMJ, Slingerland CJ, Veraar S, Lok S, Martin NI. Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens. ACS Infect Dis. 2021 Dec 10;7(12):3314-3335. doi: 10.1021/acsinfecdis.1c00466. Epub 2021 Nov 12. PMID: 34766746; PMCID: PMC8669655.
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ACS Infect Dis. 2021 Dec 10;7(12):3314-3335. doi: 10.1021/acsinfecdis.1c00466. Epub 2021 Nov 12.

Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens.

ACS infectious diseases

Charlotte M J Wesseling, Cornelis J Slingerland, Shanice Veraar, Samantha Lok, Nathaniel I Martin

Affiliations

  1. Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 BE Leiden, The Netherlands.

PMID: 34766746 PMCID: PMC8669655 DOI: 10.1021/acsinfecdis.1c00466

Abstract

Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure-activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as

Keywords: antibiotic synergy; bis-amidines; checkerboard assays; outer membrane disruption

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