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1. WO2020232534 - HOMODIMERIC TOBRAMYCIN ADJUVANT REPURPOSES NOVOBIOCIN AS AN EFFECTIVE ANTIBACTERIAL AGENT AGAINST GRAM-NEGATIVE BACTERIA

Publication Number WO/2020/232534
Publication Date 26.11.2020
International Application No. PCT/CA2020/050656
International Filing Date 15.05.2020
IPC
C07H 15/26 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
15Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
26Acyclic or carbocyclic radicals, substituted by hetero rings
A61K 47/54 2017.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
54the modifying agent being an organic compound
A61P 31/04 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
31Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
04Antibacterial agents
C07H 5/06 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
5Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
04to nitrogen
06Aminosugars
CPC
A61K 47/54
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
54the modifying agent being an organic compound
A61P 31/04
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
31Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
04Antibacterial agents
C07H 15/26
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
15Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
26Acyclic or carbocyclic radicals, substituted by hetero rings
Applicants
  • UNIVERSITY OF MANITOBA [CA]/[CA]
Inventors
  • SCHWEIZER, Frank
  • IDOWU, Temilolu
Agents
  • ADE & COMPANY INC.
Priority Data
62/849,26417.05.2019US
62/905,86325.09.2019US
62/993,98724.03.2020US
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) HOMODIMERIC TOBRAMYCIN ADJUVANT REPURPOSES NOVOBIOCIN AS AN EFFECTIVE ANTIBACTERIAL AGENT AGAINST GRAM-NEGATIVE BACTERIA
(FR) NOVOBIOCINE ADAPTÉE D'ADJUVANT DE TOBRAMYCINE HOMODIMÈRE SERVANT D'AGENT ANTIBACTÉRIEN EFFICACE CONTRE DES BACTÉRIES À GRAM NÉGATIF
Abstract
(EN)
Low permeability across the outer membrane is a major reason why most antibiotics are ineffective against Gram-negative bacteria. Agents that permeabilize the outer membrane are typically toxic at their effective concentrations. Here, we report the development of a broad-spectrum homodimeric tobramycin adjuvant that is non-toxic and more potent than the gold standard permeabilizing agent, polymyxin B nonapeptide. In pilot studies, the adjuvant confers potent bactericidal activity on novobiocin against Gram-negative bacteria, including carbapenem-resistant and colistin-resistant strains bearing plasmid-borne mcr-1 genes. Resistance development to the combination was significantly reduced, relative to novobiocin alone, and there was no induction of cross-resistance to other antibiotics, including the gyrase-acting fluoroquinolones. Tobramycin homodimer may allow the use of lower doses of novobiocin, overcoming its twin-problem of efficacy and toxicity.
(FR)
Une faible perméabilité à travers la membrane externe est une raison majeure pour laquelle la plupart des antibiotiques sont inefficaces contre les bactéries à Gram négatif. Des agents qui rendent la membrane externe perméable sont typiquement toxiques à des concentrations efficaces. La présente invention concerne le développement d'un adjuvant de tobramycine homodimère à large spectre qui est non toxique et plus puissant que l'agent de perméabilisation standard par excellence, le nonapeptide de polymyxine B. Dans des études pilotes, l'adjuvant confère une puissante activité bactéricide à la novobiocine contre des bactéries à Gram négatif, y compris des souches résistantes aux carbapénèmes et résistantes à la colistine portant des gènes mcr-1 à base de plasmide. Le développement de résistance à la combinaison a été réduit de manière significative, par rapport à la novobiocine seule, sans induire une résistance croisée à d'autres antibiotiques, y compris des fluoroquinolones à action gyrase. L'homodimère de tobramycine peut permettre l'utilisation de doses inférieures de novobiocine, ce qui permet de résoudre un double problème d'efficacité et de toxicité.
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