Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy

We describe the design and attributes of a linear pentapeptide-like derivative (C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics>...

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Autores principales:	Fadia Zaknoon, Ohad Meir, Amram Mor
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	antibiotic resistance innate immunity synergism of action peptidomimetics mechanism of action Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/f1a1fe3b40084ceda48bc3394cc22e21
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spelling	oai:doaj.org-article:f1a1fe3b40084ceda48bc3394cc22e212021-11-25T18:42:16ZMechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy10.3390/pharmaceutics131119471999-4923https://doaj.org/article/f1a1fe3b40084ceda48bc3394cc22e212021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1947https://doaj.org/toc/1999-4923We describe the design and attributes of a linear pentapeptide-like derivative (C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O) screened for its ability to elicit bactericidal competences of plasma constituents against Gram-negative bacteria (GNB). In simpler culture media, the lipopeptide revealed high aptitudes to sensitize resilient GNB to hydrophobic and/or efflux-substrate antibiotics, whereas in their absence, C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O only briefly delayed bacterial proliferation. Instead, at low micromolar concentrations, the lipopeptide has rapidly lowered bacterial proton and ATP levels, although significantly less than upon treatment with its bactericidal analog. Mechanistic studies support a two-step scenario providing a plausible explanation for the lipopeptide’s biological outcomes against GNB: initially, C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O permeabilizes the outer membrane similarly to polymyxin B, albeit in a manner not necessitating as much LPS-binding affinity. Subsequently, C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O would interact with the inner membrane gently yet intensively enough to restrain membrane-protein functions such as drug efflux and/or ATP generation, while averting the harsher inner membrane perturbations that mediate the fatal outcome associated with bactericidal peers. Preliminary in vivo studies where skin wound infections were introduced in mice, revealed a significant efficacy in affecting bacterial viability upon topical treatment with creams containing C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O, whereas synergistic combination therapies were able to secure the pathogen’s eradication. Further, capitalizing on the finding that C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O plasma-potentiating concentrations were attainable in mice blood at sub-maximal tolerated doses, we used a urinary tract infection model to acquire evidence for the lipopeptide’s systemic capacity to reduce the kidney’s bacterial loads. Collectively, the data establish the role of C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O as a compelling antibacterial potentiator and suggest its drug-like potential.Fadia ZaknoonOhad MeirAmram MorMDPI AGarticleantibiotic resistanceinnate immunitysynergism of actionpeptidomimeticsmechanism of actionPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1947, p 1947 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antibiotic resistance innate immunity synergism of action peptidomimetics mechanism of action Pharmacy and materia medica RS1-441
spellingShingle	antibiotic resistance innate immunity synergism of action peptidomimetics mechanism of action Pharmacy and materia medica RS1-441 Fadia Zaknoon Ohad Meir Amram Mor Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy
description	We describe the design and attributes of a linear pentapeptide-like derivative (C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O) screened for its ability to elicit bactericidal competences of plasma constituents against Gram-negative bacteria (GNB). In simpler culture media, the lipopeptide revealed high aptitudes to sensitize resilient GNB to hydrophobic and/or efflux-substrate antibiotics, whereas in their absence, C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O only briefly delayed bacterial proliferation. Instead, at low micromolar concentrations, the lipopeptide has rapidly lowered bacterial proton and ATP levels, although significantly less than upon treatment with its bactericidal analog. Mechanistic studies support a two-step scenario providing a plausible explanation for the lipopeptide’s biological outcomes against GNB: initially, C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O permeabilizes the outer membrane similarly to polymyxin B, albeit in a manner not necessitating as much LPS-binding affinity. Subsequently, C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O would interact with the inner membrane gently yet intensively enough to restrain membrane-protein functions such as drug efflux and/or ATP generation, while averting the harsher inner membrane perturbations that mediate the fatal outcome associated with bactericidal peers. Preliminary in vivo studies where skin wound infections were introduced in mice, revealed a significant efficacy in affecting bacterial viability upon topical treatment with creams containing C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O, whereas synergistic combination therapies were able to secure the pathogen’s eradication. Further, capitalizing on the finding that C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O plasma-potentiating concentrations were attainable in mice blood at sub-maximal tolerated doses, we used a urinary tract infection model to acquire evidence for the lipopeptide’s systemic capacity to reduce the kidney’s bacterial loads. Collectively, the data establish the role of C<sub>14(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">ω</mi></semantics></math></inline-formula>5)</sub>OOc<sub>10</sub>O as a compelling antibacterial potentiator and suggest its drug-like potential.
format	article
author	Fadia Zaknoon Ohad Meir Amram Mor
author_facet	Fadia Zaknoon Ohad Meir Amram Mor
author_sort	Fadia Zaknoon
title	Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy
title_short	Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy
title_full	Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy
title_fullStr	Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy
title_full_unstemmed	Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy
title_sort	mechanistic studies of antibiotic adjuvants reducing kidney’s bacterial loads upon systemic monotherapy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f1a1fe3b40084ceda48bc3394cc22e21
work_keys_str_mv	AT fadiazaknoon mechanisticstudiesofantibioticadjuvantsreducingkidneysbacterialloadsuponsystemicmonotherapy AT ohadmeir mechanisticstudiesofantibioticadjuvantsreducingkidneysbacterialloadsuponsystemicmonotherapy AT amrammor mechanisticstudiesofantibioticadjuvantsreducingkidneysbacterialloadsuponsystemicmonotherapy
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Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy

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