Synthesis of novel serine β-lactamase inhibitors

Thesis

The widespread emergence of bacterial resistance to β-lactam antibiotics, driven primarily by serine β-lactamases (SBLs), continues to threaten the clinical utility of this cornerstone class of antibacterial agents. Although β-lactamase inhibitors such as sulbactam and tazobactam have historically restored the activity of partner antibiotics, their effectiveness has been eroded by the proliferation of inhibitor-resistant enzymes, particularly class C (AmpC) and class D (OXA) β-lactamases. Consequently, there remains a pressing need for new inhibitor scaffolds that combine potent enzyme inhibition with improved chemical stability and tunable physicochemical properties.

This thesis explores sulfoximine substitution on the penam scaffold as a strategy to expand the chemical and biological properties of β-lactamase inhibitors. Sulfoximines offer distinct advantages over classical sulfones, including stereochemical control, dual hydrogen-bond donor/acceptor capability, and enhanced opportunities for structural diversification. Leveraging recent advances in nitrene-transfer chemistry, robust and stereocontrolled synthetic routes to penam-sulfoximines were developed from sulbactam-derived sulfoxides. Both (S)- and (R)-configured penam sulfoximines were prepared, including synthetically challenging NH-sulfoximines that closely mimic the parent sulbactam framework. Single-crystal X-ray diffraction confirmed stereochemical integrity and structural assignments.

The scope and limitations of sulfoximine N-functionalization were systematically investigated, enabling access to amide, urea, and N-aryl derivatives while revealing intrinsic stability constraints of the penam core under basic or reductive conditions. These studies establish a versatile synthetic platform for the generation of structurally diverse penam-sulfoximines suitable for biological evaluation.

Biochemical and microbiological studies demonstrated that penam-sulfoximines are potent inhibitors of clinically relevant SBLs, including AmpC and OXA-type enzymes. A free NH penam-sulfoximine displayed particularly strong enzyme inhibition and measurable antibacterial activity against Acinetobacter baumannii, supported by enzyme inhibition assays, protein-binding studies, antimicrobial susceptibility testing, and structural characterization of enzyme–inhibitor complexes. However, many substituted sulfoximines exhibited reduced stability under physiological conditions, highlighting a trade-off between potency and chemical robustness.

Overall, this work establishes penam-sulfoximines as a chemically accessible and biologically active class of β-lactamase inhibitors, delineates key structure–stability–activity relationships, and provides a foundation for the future design of sulfoximine-based agents targeting resistant Gram-negative pathogens.

Authors: Ho, JY

• DOI: 10.5287/ora-o8kqy1gwo
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: antimicrobial resistance; AmpC β-lactamase; serine β-lactamases; OXA-10; sulbactam; antibacterial agents; penam sulfoximines; antibiotic resistance; TEM-116; sulfoximines; OXA-48; antibacterial drug discovery; medicinal chemistry; structure-based drug design; β-lactamase inhibitors; covalent inhibition; enzyme inhibition; organic synthesis; β-lactams; Acinetobacter baumannii
• Subjects: Chemistry; Biochemistry; Pharmaceutical chemistry; Drug resistance in microorganisms; Antibiotics; Synthesis; Chemistry, Organic; Microbiology