Author:
Meir Ohad,Zaknoon Fadia,Mor Amram
Abstract
AbstractScarcity of effective treatments against sepsis is daunting, especially under the contemporary standpoints on antibiotics resistance, entailing the development of alternative treatment strategies. Here, we describe the design and antibiotic adjuvant properties of a new lipopeptide-like pentamer, decanoyl-bis.diaminobutyrate-aminododecanoyl-diaminobutyrate-amide (C10BBc12B), whose sub-maximal tolerated doses combinations with inefficient antibiotics demonstrated systemic efficacies in murine models of peritonitis-sepsis and urinary-tract infections. Attempts to shed light into the mechanism of action using membrane-active fluorescent probes, suggest outer-membrane interactions to dominate the pentamer’s adjuvant properties, which were not associated with typical inner-membrane damages or with delayed bacterial growth. Yet, checkerboard titrations with low micromolar concentrations of C10BBc12B exhibited unprecedented capacities in potentiation of hydrophobic antibiotics towards Gram-negative ESKAPE pathogens, with an apparent low propensity for prompting resistance to the antibiotics. Assessment of the pentamer’s potentiating activities upon efflux inhibition incites submission of a hitherto unreported, probable action mechanism implicating the pentamer’s de-facto capacity to hijack bacterial efflux pumps for boosting its adjuvant activity through repetitive steps including outer-membrane adhesion, translocation and subsequent expulsion.
Funder
Israel Science Foundation
Publisher
Springer Science and Business Media LLC
Reference72 articles.
1. Angus, D. C. & Van Der Poll, T. Severe sepsis and septic shock. N. Engl. J. Med. 369, 840–851 (2013).
2. Cohen, J. et al. Sepsis: a roadmap for future research. Lancet Infect. Dis. 15, 581–614 (2015).
3. WHO. Current evidence, identifying gaps and future directions: global report on the epidemiology and burden of sepsis (2020).
4. Rudd, K. E. et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 395, 200–211 (2020).
5. Annane, D. et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA - J. Am. Med. Assoc. 301, 2362–2375 (2009).
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