SAMRC Award - University of Oxford

Lead Research Organisation: University of Oxford

Abstract

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Technical Summary

Recent surveillance data reveals that the incidence of serious gram-negative infections is increasing in Sub-
Saharan Africa1. Unfortunately, treatment options for these Gram-negative infections using ß-lactams, which remain
the most important class of antibiotics, is significantly compromised by the presence of serine- and/or zinc metallo-ß-
lactamases in clinical strains of E. coli, K. pneumoniae, E. cloacae, A. baumannii and P. aeruginosa2,3. Worldwide, >1800
ß-lactamases have been identified that can reduce or ablate the efficacy of ß-lactam antibiotics via lactam hydrolysis3.
There is a clear need for more treatment options to address this health threat, both in South Africa and globally. Most
pressing is a clinically useful agent capable of treating infections caused by a Gram-negative bacteria containing a New
Delhi metallo-ß -lactamase (NDM-1), imipenem-style metallo-ß -lactamase (IMP) or Verona integron-encoded metallo-
ß-lactamase (VIM). The monobactam Aztreonam is the only ß-lactam which is relatively stable to metallo-ß-
lactamase2; however, it is labile to serine ß-lactamases. Hence new monobactams that are more stable to serine ß-
lactamases will aid in the fight against resistant gram-negative bacteria, especially those classified as carbapenemaseresistant
Enterobacteriaceae (CRE).
Specifically, this project will focus on building capacity and collaboration between South Africa and the UK within
the context of research addressing two main needs in the fight against antimicrobial resistance (AMR):
1) Optimization of the recently discovered novel cyclic boronate dual serine- and metallo-ß-lactamase inhibitors that
can be used singly or in combination with existing antibiotics to treat serious Gram-negative infections
2) Identification of novel monocyclic ß-lactam antibiotics for the treatment of serious Gram-negative infections
One aspect of the work will focus on H3D profiling the drug metabolism and pharmacokinetic (DMPK) properties
of the novel cyclic boronates discovered in the labs of Schofield and Fishwick5. DMPK study results will be jointly
discussed among the collaborators to decide if the current cyclic boronates can be progressed to an animal efficacy
study, or if further optimization of the series needs to be done. This effort will provide an opportunity for researchers
in the collaborating teams to learn about the compound characteristics necessary for a successful Gram-negative
infection animal study and to determine optimal dosing regimens for an eventual combination therapy.
At the same time, work will begin in order to build a strong knowledge base on Penicillin Binding Protein (PBP)
structure-activity relationships (SAR) and how that SAR and available PBP X-ray structures can be used in conjunction
with the recent high quality hits obtained from X-ray fragment screening against PBP-3 and VIM-2 to design improved
novel monobactam PBP inhibitors resistant to ß-lactamases. Synthesis of the newly designed monobactams will be
carried out and biochemical and microbiological profiling performed against a panel of PBPs and gram-negative
bacteria to test the validity of the design ideas.

Publications

10 25 50
 
Description SAMRC Collaboration 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution DMPK study results will be jointly discussed among the collaborators to decide if the current cyclic boronates can be progressed to an animal efficacy study, or if further optimization of the series needs to be done. This effort will provide an opportunity for researchers in the collaborating teams to learn about the compound characteristics necessary for a successful Gram-negative infection animal study and to determine optimal dosing regimens for an eventual combination therapy
Collaborator Contribution work will begin in order to build a strong knowledge base on Penicillin Binding Protein (PBP) structure-activity relationships (SAR) and how that SAR and available PBP X-ray structures can be used in conjunction with the recent X-ray fragment screening against PBP-3 to design improved novel monobactam PBP inhibitors resistant to ?-lactamases. Synthesis of the newly designed monobactams will be carried out and biochemical and microbiological profiling performed against a panel of PBPs and gram-negative bacteria to test the validity of the design ideas.
Impact Publication
Start Year 2017
 
Description Astbury Mini Symposium on Antimicrobial Resistance, Leeds 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact "Working towards successors for the ß-lactams"
Year(s) Of Engagement Activity 2017
 
Description Astbury Mini Symposium on Antimicrobial Resistance, Leeds 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact "Working towards successors for the ß-lactams"
Year(s) Of Engagement Activity 2018
 
Description Drug Discovery in Academia Conference, Munich, Germany 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact "Targeting Metallo-Enzymes for Antibiotic Resistance and Human Diseases"
Year(s) Of Engagement Activity 2018
 
Description European Federation for Medicinal Chemistry conference, New Orleans 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Towards boron based antibiotics and beta-lactamase inhibitors
Year(s) Of Engagement Activity 2018
 
Description ICMR2017, Akita University, Japan 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact ICMR2017, Akita University, Japan.
Plenary lecture
"From penicillins to oxygen sensing in humans"
Year(s) Of Engagement Activity 2017
 
Description Royal Society of Chemistry Conference on Mastering Medicinal Chemistry, Glasgow 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Study participants or study members
Results and Impact Keynote Lecture - "Inhibiting Enzymes - from Bacteria to Humans"
Year(s) Of Engagement Activity 2018
 
Description Seminar - Durham University 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Seminar Title - From Anitbiotics to Oxygen Sensing and Back Again
Year(s) Of Engagement Activity 2017
 
Description Seminar - Princeton University 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Seminar - From the Chemistry of Penicillin to Oxygen Sensing in Humans
Year(s) Of Engagement Activity 2017
 
Description Seminar at Institute Pasteur, Paris 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact "From Penicillins to Epigenetics - Adventures at the Interface of Chemistry and Biology"
Year(s) Of Engagement Activity 2018
 
Description Seminar at University College Cork, Ireland 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact From antibiotics to hypoxia sensing and back again"
Year(s) Of Engagement Activity 2017
 
Description Talk at SGC, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Supporters
Results and Impact "Towards New Antibiotics - Targeting Penicillin Binding Proteins"
Year(s) Of Engagement Activity 2017
 
Description Talk for OU Biochemical Society, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact "From Antibiotics to Oxygen Sensing and Back Again"
Year(s) Of Engagement Activity 2017
 
Description Technische Universität Darmstadt Seminar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact "From Penicillins to Oxygen Sensing"
Year(s) Of Engagement Activity 2018
 
Description The American Society of Pharmacognosy Annual Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact ENZYMES THAT MAKE AND BREAK ß-LACTAMS


The lecture will describe mechanistic and inhibition studies on enzymes involved in ß-lactam biosynthesis and hydrolysis. It will aim to show how a desire to understand how these enzymes work led to the identification of unanticipated roles for homologues of the bacterial roles in humans, including in the regulation of protein biosynthesis and nucleic acid repair. Recently, this work has led to the identification of new mechanisms for antibiotic resistance. Work on the inhibition of metallo ß-lactamases and other enzymes involved in antibiotic resistance will be described.
Year(s) Of Engagement Activity 2018
 
Description The American Society of Pharmacognosy Annual Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact "Enzymes that make and break ß-lactams"
Year(s) Of Engagement Activity 2018
 
Description UQ Bertram Dillon Steele Lecture in Brisbane 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact From Penicillins to Epigenetics - Adventures at the Interface of Chemistry and Biology
Year(s) Of Engagement Activity 2018