BIOSYNTHESIS OF ANTIBIOTICS
CONTENTS CHAPTER 1 TREATMENT OF CLOSTRIDIUM DIFFICILE INFECTIONS 1 1 BACKGROUND 1 2 CDI SYMPTOMS AND PROGRESSION 1 3 RELAPSE 1 4 DIAGNOSIS 1 5 PREVENTION MEASURES—GENERAL HOSPITAL PRACTICE AND OTHER PREVENTION METHODS 1 6 CURRENT TREATMENT AND ANTIBIOTICS 1 6 1 ANTI-TOXINS 1 6 2 VACCINES 1 6 3 ANTI-GERMINANTS 1 6 4 FECAL TRANSPLANTATION 1 6 5 PROBIOTICS 1 7 CONCLUSION REFERENCES CHAPTER 2 TARGETING PURINE BIOSYNTHESIS FOR ANTIBACTERIAL DRUG DESIGN 2 1 INTRODUCTION 2 1 1 THE DE NOVO PURINE NUCLEOTIDE BIOSYNTHESIS PATHWAY 2 1 2 THE PURINE CONVERSION PATHWAYS 2 1 3 THE PURINE SALVAGE PATHWAYS 2 1 4 AVAILABILITY OF PURINE BASES AND NUCLEOSIDES 2 1 5 THE COMPLEX INTERPLAY BETWEEN SALVAGE PATHWAYS AND PRECURSOR AVAILABILITY 2 2 THE ESSENTIALITY OF ENZYMES OF THE PURINE BIOSYNTHETIC PATHWAYS 2 2 1 ESSENTIALITY OF PURINE NUCLEOTIDE BIOSYNTHESIS FOR GROWTH IN RICH MEDIA 2 2 2 ESSENTIALITY OF PURINE NUCLEOTIDE BIOSYNTHESIS DURING INFECTION 2 2 3 INHIBITORS MAY NOT HAVE THE SAME PHENOTYPES AS GENE KNOCKOUTS 2 2 4 THE PROBLEM OF RESISTANCE 2 3 PROGRESS TARGETING THE ENZYMES OF DE NOVO PURINE NUCLEOTIDE BIOSYNTHESIS 2 4 PROGRESS TARGETING ENZYMES IN THE PURINE NUCLEOTIDE CONVERSION PATHWAYS 2 4 1 IMPDH STRUCTURE AND MECHANISM 2 4 2 PROKARYOTIC AND EUKARYOTIC IMPDHS: A COMPARATIVE ANALYSIS OF RATIONAL DRUG DESIGN 2 4 3 REPURPOSING CRYPTOSPORIDIUM IMPDH INHIBITORS AS ANTIBIOTICS 2 5 CONCLUSION ACKNOWLEDGEMENTS CHAPTER 3 INHIBITORS OF BIOFILM PRODUCTION 3 1 INTRODUCTION 3 2 BIOFILMS 3 3 STRATEGIES FOR COMBATING BIOFILMS 3 3 1 QUORUM SENSING INHIBITORS 3 3 2 INHIBITORS OF AHL BASED QUORUM SENSING AS BIOFILM INHIBITORS 3 3 3 INHIBITORS OF AIP-BASED QUORUM SENSING AS BIOFILM INHIBITORS 3 3 4 INHIBITORS OF AI-2 BASED QUORUM SENSING AS BIOFILM INHIBITORS 3 4 INHIBITION OF BACTERIAL SIGNALING PATHWAYS 3 4 1 INTERFERENCE WITH C-DI-GMP SIGNALING TO INHIBIT BIOFILM FORMATION 3 4 2 INHIBITION OF INDOLE SIGNALING PATHWAYS TO PREVENT BIOFILM FORMATION 3 4 3 INHIBITION OF TWO-COMPONENT SIGNAL TRANSDUCTION SYSTEMS (TCS) TO PREVENT BIOFILM FORMATION 3 4 4 INHIBITION OF OTHER SIGNALING PATHWAYS TO PREVENT BIOFILM FORMATION 3 5 IDENTIFICATION OF NATURAL PRODUCTS AND ANALOGUES THAT PREVENT BIOFILM FORMATION 3 5 1 PLANT NATURAL PRODUCTS AND ANALOGUES THAT PREVENT BIOFILM FORMATION 3 5 2 MARINE NATURAL PRODUCTS AND ANALOGUES THAT PREVENT BIOFILM FORMATION 3 5 3 OTHER NATURAL PRODUCTS THAT PREVENT BIOFILM FORMATION 3 6 ANTIMICROBIAL PEPTIDES (AMPS) THAT PREVENT BIOFILM FORMATION 3 7 INHIBITION OF EFFLUX TO PREVENT BIOFILM FORMATION 3 8 MATRIX DEGRADATION TO PREVENT BIOFILM FORMATION 3 9 CONCLUSIONS CHAPTER 4 NARROW SPECTRUM ANTIBACTERIAL AGENTS 4 1 INTRODUCTION 4 2 NATURAL PRODUCTS 4 3 SYNTHETIC AND TARGET-BASED APPROACHES 4 4 FUTURE PROSPECTS 4 5 CONCLUSIONS CHAPTER 5 THE LPS TRANSPORT PATHWAY: A NEW TARGET FOR THE DEVELOPMENT OF GRAM-NEGATIVE ANTIBIOTICS 5 1 INTRODUCTION 5 2 LIPOPOLYSACCHARIDE (LPS) AND THE GRAM-NEGATIVE CELL ENVELOPE 5 3 THE LPS BIOSYNTHESIS PATHWAY 5 3 1 KDO2-LIPID A 5 3 2 CORE POLYSACCHARIDE 5 3 3 O-ANTIGEN 5 4 LPS MODIFICATION AND ITS ROLE IN GRAM-NEGATIVE BACTERIAL PERSISTENCE 5 5 LPS TRANSPORT: THE LPT PATHWAY 5 5 1 EXTRACTION OF LPS FROM THE IM 5 5 2 TRAVERSING THE PERIPLASM: THE LPTA PROTEIN BRIDGE 5 5 3 LPS INSERTION INTO THE OM 5 6 LPS TRANSPORT AS A NEW TARGET FOR THE DEVELOPMENT OF GRAM-NEGATIVE ANTIBIOTICS 5 7 CONCLUSIONS CHAPTER 6 THE DISCOVERY OF TEIXOBACTIN 6 1 INTRODUCTION 6 2 CULTIVATING THE UNCULTURABLE – THE ICHIP 6 3 TEIXOBACTIN – A NOVEL ANTIBIOTIC 6 4 STRUCTURAL DETERMINATION OF TEIXOBACTIN 6 5 SYNTHESIS OF TEIXOBACTIN AND ANALOGUES 6 6 CONCLUSION CHAPTER 7 EMERGING TARGETS IN ANTI-TUBERCULAR DRUG DESIGN 7 1 INTRODUCTION 7 1 1 THE BIOLOGY AND PATHOLOGY OF TB 7 1 2 CURRENT DRUG TARGETS 7 1 3 RESISTANCE RELATED TO TB 7 2 DISCOVERY AND VALIDATION OF NOVEL DRUG TARGETS IN TB 7 2 1 TARGETS INVOLVED IN MYCOBACTERIUM TUBERCULOSIS CELL ENVELOPE BIOSYNTHESIS 7 2 2 TARGETS INVOLVED IN MYCOBACTERIUM TUBERCULOSIS GENERAL METABOLISM 7 3 SYNERGISTIC DRUG COMBINATION THERAPY 7 3 1 UNRELATED COMPOUNDS 7 3 2 INHIBITORS OF RESISTANCE ENZYMES 7 3 3 P2X7 RECEPTOR AGONIST 7 4 CONCLUSION AND PERSPECTIVES CHAPTER 8 ANTIBACTERIAL LEADS TARGETING ISOPRENOID BIOSYNTHESIS 8 1 INTRODUCTION 8 2 TARGETING THE MVA PATHWAY 8 2 1 HISTORIC COMPOUNDS INHIBITING THE MVA PATHWAY 8 2 2 SCREENING FOR INHIBITORS OF THE MVA PATHWAY IN BACTERIA 8 2 3 TARGETING THE GHMP KINASE FAMILY MEMBERS OF THE MVA PATHWAY 8 3 TARGETING THE MEP PATHWAY 8 3 1 HISTORIC COMPOUNDS INHIBITING THE MEP PATHWAY 8 3 2 INHIBITING DXS 8 3 3 INHIBITING ISPC 8 3 4 INHIBITING ISPD 8 3 5 INHIBITING ISPE 8 3 6 INHIBITING ISPF 8 3 7 INHIBITING ISPG AND ISPH 8 4 ALTERNATE TARGETS UTILIZING IPP PRECURSORS 8 4 1 INHIBITING IDI 8 4 2 INHIBITING UPPS 8 4 3 INHIBITING STAPHYLOXANTHIN BIOSYNTHESIS 8 5 CONCLUSIONS