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Molecular Mechanisms Underlying Resistance to Clinical Combination Therapy in Acinetobacter baumannii

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posted on 2022-10-17, 23:46 authored by Natasha DelgadoNatasha Delgado

Nosocomial A. baumannii infections are a rising problem globally. Remarkable genome plasticity facilitates the rapid acquisition of resistance determinants and swift adaptation to new antibiotic therapies. Clinical A. baumannii frequently possess an impressively MDR phenotype, which can make it extremely difficult to treat with anything but our last line therapies. In the absence of new therapeutics, combination therapy has many advantages that make it extremely enticing for sustainably treating drug resistant A. baumannii. These include exploiting synergy, lowering dosages to minimise side effects, revitalising our existing drugs; and broadened antimicrobial targeting. Concerningly, despite its widespread application, very little is known about how resistance develops in response to combination therapy. One combination that is commonly used in Australian hospitals is trimethoprim and sulfamethoxazole. The aim of this project was to identify genes involved in resistance to this combination in two strains of A. baumannii; the reference strain ATCC 17978 and a clinical strain BAL062. Two complementary sequence-based approaches were employed; Directed Evolution and Transposon Directed Insertion Site Sequencing (TraDIS). These techniques identified a range expected resistance genes (e.g. RND efflux component and regulator genes) as well as some interesting novel resistance determinants.


Table of Contents

Chapter 1: Introduction -- Chapter 2: Materials and Methods -- Chapter 3: Antimicrobial Susceptibility Profiling -- Chapter 4: Identification of resistance mutations to single antibiotics and their combinations using Directed Evolution -- Chapter 5: Constructing a high-density transposon mutant library in ATCC 17978 -- Chapter 6: Defining genes involved in resistance to antibiotic combinations -- Chapter 7: Conclusion -- References -- Supplementary Data


A thesis in fulfilment for the degree of Master of Research

Awarding Institution

Macquarie University

Degree Type

Thesis MRes


Thesis MRes, Macquarie University, Department of Molecular Sciences, 2020

Department, Centre or School

Department of Molecular Sciences

Year of Award


Principal Supervisor

Amy Cain


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