Development of Novel Scaffolds Acting Against Priority Antibiotic-resistant Bacteria

Abstract

Bacterial resistance towards clinically used antibiotics continues to emerge and represents an increasing threat to human health. To address growing antibiotics resistance globally, the World Health Organization (WHO) has published a list of antibiotic-resistant priority pathogens. The major objective of publishing this list is to guide and promote research and development (R&D) for treating these priority pathogens. The suggested long-term solution by WHO is to explore new classes of antibiotics with novel modes of action. This thesis describes the results of a research program aimed at investigating novel scaffolds acting against WHO priority antibiotic-resistant bacteria. The work that forms the major part of the research described in the first part (Chapters 2 to 4) of the thesis, was directed towards development of simplified analogues of nucleoside antibiotics; a class of bacterial derived natural products acting against novel target, the MraY enzyme (translocase I). Due to their promising antibacterial activity against a broad spectrum of Gram-positive as well as Gram-negative bacteria, nucleoside antibiotics have been considered as promising lead structures for the development of novel antibacterial agents. Based on their structural characteristics, nucleoside antibiotics have been classified into four classes: i) uridylpeptides, ii) ribosamino-uridines, iii) tunicamycins and iv) capuramycins. In this work, three nucleoside antibiotics including mureidomycin (uridylpeptide class), muraymycins (ribosamino-uridine class) and caprazamycins (ribosamino-uridine class) were selected for investigating their simplified analogues. Chapter 2 describes development towards mureidomycin nucleoside antibiotics. The chapter begins with uridine scaffold optimisation study by increasing hydrophobicity on to its C-5 position. By using the established solid-phase Suzuki-Miyaura cross-coupling reaction, we have rapidly synthesised a library of 20 different C-5 substituted uridine analogues. Following to that, through preliminary biological screening of the C-5 substituted uridine analogues, we have been able to generate our proof of concept that increasing hydrophobicity on to the C-5 position of uridine leads to increase antibacterial activity. At this stage, this optimised synthetic protocol is ready to extrapolate further for late stage modification of mureidomycin after having linked with the peptidyl western zone. Chapter 3 outlines our systematic approach towards the synthesis of simplified analogues of muraymycin nucleoside antibiotic. Several methodologies are reported for synthesis of the core glycyluridine structure of muraymycins. It appears from the review of literature that gaining access to this core glycyluridine is not as straightforward as envisaged. Therefore, in this work, we designed simplified muraymycin analogues by replacing the complex glycyluridine with a simplified serine template. This chapter reports our detailed SAR study for minimum structural requirement of the simplified serine template with the outcome of three active hit compounds against WHO priority antibiotic-resistant bacteria. Detailed investigation of simplified caprazamycin analogues is the theme in Chapter 4. This work was initiated with our published review of literature, carried out to reveal the essential pharmacophores present in caprazamycin nucleoside antibiotics. The SAR analysis suggested that a simplified cyclic ring in place of the complex diazepanone ring, linked with key pharmacophores would engender a potent simplified caprazamycin analogue. Based on the SAR analysis, we designed 1,3,5-trisubstituted pyrazoles as a simplified cyclic core to hold key pharmacophores similar to the caprazamycin natural product. This chapter comprises of a detailed discussion of our attempts to synthesise 1,3,5-trisubstituted pyrazoles for reducing complexity of caprazamycin natural products. The second area of research in this thesis, described in Chapter 5, was based on investigating small molecules active against WHO priority pathogens. The present work was focused on building pyrazole linked phenylthiazole analogues. A library of total 24 novel pyrazole linked phenylthiazole compounds were synthesised to explore structure-activity relationships. Chapter 5 finishes with a detailed discussion of the antibacterial activity observed against methicillin-resistant Staphylococcus aureus (MRSA).