Exploring aogacillin: Analog synthesis and bioactivity assessment against resistant pathogens Open Access
Isakov, Audrey (Summer 2026)
Abstract
Antibiotic resistance is a growing global crisis, rendering once-effective treatments powerless
against infections. The misuse and overuse of antibiotics has accelerated the emergence of resistant pathogens, leading to higher mortality rates and increased healthcare costs. Preliminary findings suggest that the natural product aogacillin enhances the efficacy of existing antibiotics by preventing the development of resistance mechanisms. It is hypothesized that aogacillin combats resistance by blocking an acylation process that drives bacterial resistance mechanisms. To enable this bioactivity profiling, synthesis of aogacillin and structurally related analogs is conducted. In particular, structural features influencing 3-dimensional conformation provides information regarding significant active site interactions. Robust synthesis of these analogs and their mechanisms can pave the way for groundbreaking strategies to curb resistance and restore the effectiveness of vital drugs.
Table of Contents
Table of Contents
Chapter 1: Antimicrobial resistance and novel strategies for therapeutics
1.1 Introduction to Antimicrobial Resistance ............................................................................8
1.2 Aminoglycoside-modification resistance pathways ..........................................................10
1.3 Introduction to Methicillin-resistant S. aureus and Arbekacin ...........................................15
Chapter 2: The simplified analog approach
2.1 Aogacillins understood activity and hypothesized method of action ..................................17
2.2 Simplified analog synthesis ...............................................................................................20
Chapter 3: Efforts towards the natural product aogacillin
3.1 Analysis of structural geometry .........................................................................................25
3.2 Efforts towards stereospecificity ........................................................................................26
Chapter 4: The total Synthesis of substituted analogs of aogacillin
4.1 Introduction to a substituted analog target .........................................................................29
4.2 Attempted total synthesis ..................................................................................................31
4.3 Biological activity of analog library ...................................................................................33
4.4 Reflections and Conclusions ..............................................................................................35
Supporting Information for Chapter 2 ............................................................................................36
Supporting Information for Chapter 3 ............................................................................................41
Supporting Information for Chapter 4 ............................................................................................43
References .....................................................................................................................................48
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