Medicinal Chemistry Strategies to Breach the Gram-Negative Bacterial Outer Membrane

Abstract

The impermeable outer membrane of Gram-negative bacteria has long been an obstacle for antibiotic development. In the face of the antibiotic resistance crisis, novel strategies to breach this membrane are crucial to combat these pathogens. This thesis investigates three complementary strategies to overcome the outer membrane from a medicinal chemistry perspective. Chapter 1 discusses the urgent need for new antibiotics, the challenges posed by Gram-negative bacteria, and the strategies that have been employed to overcome the permeability barrier of Gram-negative bacteria. Chapter 2 focuses on an aryl hydrazide outer membrane potentiator that enhances the activity of linezolid against E. coli. A series of 37 analogues were synthesized to investigate structure-activity relationships. Identified trends in the SAR study and GP-20 analogues demonstrating enhanced synergy with linezolid are described. Chapter 3 focuses on the structure activity relationship study for antibiotic potentiator O24. Development of a synthetic route enabled access to analogues investigating key areas of the lead compound. Here we describe structure activity relationship trends for O24 and the new leads which exhibit improved synergy with rifampicin against E. coli. Chapter 4 discusses the synthesis of a novel “Trojan horse” antibiotic that exploits the iron uptake pathway to enter through the outer membrane. Using siderophores identified from a high throughput screen, a synthetic route was developed to conjugate the iron chelators to a β-lactam antibiotic. The sideromycin exhibited potent activity against Gram-negative pathogens and a promising lead for future antibiotic development. Chapter 5 discusses the structure-activity relationship study of an oxime-ester antibiotic that targets the lipoprotein biosynthesis pathway. The study emphasized the importance of lipophilicity for the target protein Lgt and the resulting limitations on wild-type activity. Preliminary efforts to develop a sideromycin conjugate and ongoing work will be described.