Contents 1. Introduction 28 1.1. Advantages of the Chemical Biology Approach for the Study of Quorum Sensing Pathways 30 1.2. Important Considerations When Comparing the Results of Different Studies 31 2. AHL-Based Quorum Sensing in Gram-Negative Bacteria 31 2.1.
The introduction of effective antibacterial therapies for infectious diseases in the mid-20th century completely revolutionized clinical practices and helped to facilitate the development of modern medicine. Many potentially life-threatening conditions became easily curable, greatly reducing the incidence of death or disability resulting from bacterial infections. This overwhelming historical success makes it very difficult to imagine life without effective antibacterials; however, the inexorable rise of antibiotic resistance has made this a very real and disturbing possibility for some infections. The ruthless selection for resistant bacteria, coupled with insufficient investment in antibacterial research, has led to a steady decline in the efficacy of existing therapies and a paucity of novel structural classes with which to replace them, or complement their use. This situation has resulted in a very pressing need for the discovery of novel antibiotics and treatment strategies, the development of which is likely to be a key challenge to 21st century medicinal chemistry.
Antibiotic resistance is a global health concern and a current threat to modern medicine and society. New strategies for antibiotic drug design and delivery offer a glimmer of hope in a currently limited pipeline of new antibiotics. One strategy involves conjugating iron-chelating microbial siderophores to an antibiotic or antimicrobial agent to enhance uptake and antibacterial potency. Cefiderocol (S-649266) is a promising cephalosporin–catechol conjugate currently in phase III clinical trials that utilizes iron-mediated active transport and demonstrates enhanced potency against multi-drug resistant (MDR) Gram-negative pathogens. Such molecules demonstrate that siderophore–antibiotic conjugates could be important future medicines to add to our antibiotic arsenal. This review is written in the context of the chemical design of siderophore–antibiotic conjugates focusing on the differing siderophore, linker, and antibiotic components that make up conjugates. We selected chemically distinct siderophore–antibiotic conjugates as exemplary conjugates, rather than multiple analogues, to highlight findings to date. The review should offer a general guide to the uninitiated in the molecular design of siderophore–antibiotic conjugates.
Structurally diverse libraries of novel small molecules represent important sources of biologically active agents. In this paper we report the development of a diversity-oriented synthesis strategy for the generation of diverse small molecules based around a common macrocyclic peptidomimetic framework, containing structural motifs present in many naturally occurring bioactive compounds. Macrocyclic peptidomimetics are largely underrepresented in current small-molecule screening collections owing primarily to synthetic intractability; thus novel molecules based around these structures represent targets of significant interest, both from a biological and a synthetic perspective. In a proof-of-concept study, the synthesis of a library of 14 such compounds was achieved. Analysis of chemical space coverage confirmed that the compound structures indeed occupy underrepresented areas of chemistry in screening collections. Crucial to the success of this approach was the development of novel methodologies for the macrocyclic ring closure of chiral α-azido acids and for the synthesis of diketopiperazines using solid-supported
N
methylmorpholine. Owing to their robust and flexible natures, it is envisaged that both new methodologies will prove to be valuable in a wider synthetic context.
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