Design and synthesis of enzyme inhibitors against Gram-negative bacteria: Targeting protein secretion and lipid A biosynthesis

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Benediktsdóttir, Andrea,1990-Uppsala universitet,Institutionen för läkemedelskemi,Drug Design and Discovery (author)

Design and synthesis of enzyme inhibitors against Gram-negative bacteria : Targeting protein secretion and lipid A biosynthesis

BookEnglish2024

Publisher, publication year, extent ...

Uppsala :Acta Universitatis Upsaliensis,2024
80 s.
electronicrdacarrier

Numbers

LIBRIS-ID:oai:DiVA.org:uu-524499
ISBN:9789151320922
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-524499URI

Supplementary language notes

Language:English
Summary in:English &language:-1_t

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SwePubSwePub

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Subject category:vet swepub-contenttype
Subject category:dok swepub-publicationtype

Series

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy,1651-6192 ;351

Notes

The discovery and implementation of antibiotics for clinical use was unquestionably the greatest medical breakthrough of the 20th century. However, the widespread misuse and overuse of these antibiotics, has led to the rapid emergence and spread of antibiotic resistance. The 'ESKAPE' pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) represent a critical threat in multidrug-resistant infections. The Gram-negative species (such as E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii) are especially difficult to combat due to their dual-membrane and efficient efflux pumps, which limit the efficacy of many antibiotics. Despite significant efforts, no new antibiotic class with a new mechanism of action has been approved for Gram-negative pathogens in over five decades. New chemical classes of antibacterial compounds targeting distinct mechanisms within Gram-negative bacteria are therefore urgently called for. The studies outlined in this thesis addresses these challenges by designing and synthesising new antibacterial compounds of three distinct chemical classes, which interact with two unrealized targets, LepB and LpxH, in Gram-negative bacteria, including E. coli and K. pneumoniae. This thesis investigates the effect of macrocyclization of type I signal peptidase (LepB) inhibitors by optimizing previously studied linear lipopeptide boronic acids and esters to address their cytotoxic and hemolytic liabilities while retaining activity. This resulted in the synthesis of first-in-class P2-P1' boronic ester-linked macrocycles with modest improvement of cytotoxicity but at the cost of reduced antibacterial activity (paper I). In another optimization attempt, isosteric modification of LepB inhibitors was explored by introducing the sulfonimidamide motif into oligopeptide boronic esters, displaying potent LepB inhibitors. Prior to the synthesis of these pseudopeptides novel methods were developed to introduce sulfonimidamides into peptides on solid-phase (paper II and paper III). These studies demonstrated the potential of sulfonimidamides to alter the drug properties and which was herein compared to a corresponding sulfonamide. Additionally, the thesis describes how a new series of LpxH inhibitors, meta-sulfonamidobenzamide-based sulfonyl piperazine derivatives, were identified and prepared. This resulted in inhibitors with wild-type activity without causing hemolysis, cell toxicity or inhibition of hERG ion channel (paper IV). In summary, strategies suitable for the synthesis and optimization of new antibacterial compounds targeting two distinct Gram-negative bacterial targets, LepB and LpxH, are described in this thesis. While there was no success in separating toxicity from antibacterial activity of the LepB inhibitors, these results highlight the challenge in this task and contribute to a better understanding of the structure-activity and toxicity relationships of such inhibitors and provide strategies that could be of use in antibacterial drug discovery. The identification of the meta-sulfonamidobenzamide derivatives offer promising LpxH-targeting hits with the potential for further development in future hit-to-lead antibacterial programs.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Läkemedelskemi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medicinal Chemistry hsv//eng
Antibacterial drug discovery
Type I signal peptidase
LepB
LpxH
lipopolysaccharide biosynthesis
E. coli
structure-activity relationship
cytotoxicity
lipid A
sulfonimidamide
bioisosteres
pseudopeptides
oligopeptides
boronic acid
boronic ester
macrocycle
Medicinal Chemistry
Läkemedelskemi

Added entries (persons, corporate bodies, meetings, titles ...)

Sandström, Anja,Professor,1973-Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling(Swepub:uu)anjajoha (thesis advisor)
Karlén, Anders,ProfessorUppsala universitet,Läkemedelsdesign och läkemedelsutveckling(Swepub:uu)anderskl (thesis advisor)
Zamaratski, Edouard,DoktorUppsala universitet,Institutionen för läkemedelskemi (thesis advisor)
Brandt, Peter,DoktorUppsala universitet,Institutionen för läkemedelskemi (thesis advisor)
Haug, Bengt Erik,ProfessorDepartment of Chemistry, University of Bergen (opponent)
Uppsala universitetInstitutionen för läkemedelskemi (creator_code:org_t)

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