Antibiotics (eBook)

Claudio Gualerzi is full professor of Molecular Biology at the University of Camerino (Italy) and member of the EMBO. Following his studies at the University of Rome-La Sapienza and a postdoctoral period at the University of Pennsylvania (USA), he served as research group leader at the Max-Planck-Institute for Molecular Genetics in Berlin (Germany). He was consultant for the Lepetit Research Center in Gerenzano (Italy) and has received numerous awards and honorary lectureships, including the research prize of the Alexander von Humboldt foundation for his work on ribosome function and the discovery of novel antibiotics. Attilio Fabbretti completed his doctoral studies at the University of Camerino (Italy) where he is now a research associate in the laboratory of Molecular Biology. He received the prize of the Italian Society for General Microbiology and Microbial Biotechnology for the best PhD thesis in 2007. Letizia Brandi received her doctoral degree from the University of Catania after performing her thesis work at the University of Camerino, Italy. She served a postdoctoral period at the University of Montana (Missoula, USA) and worked as a senior scientist at Biosearch Italia, spa and Vicuron Pharmaceuticals (Gerenzano, Italy), before joining the laboratory of Molecular Biology at the University of Camerino where she is now a research associate. Cynthia Pon received her PhD from Rutgers the State University (USA). Following post-doctoral periods at the University of Pennsylvania and Hunter College of the City University of New York, she worked at the Max-Planck-Institute for Molecular Genetics in Berlin (Germany) before becoming full professor of Molecular and Microbial Genetics at the University of Camerino (Italy). Her work has focused on the mechanism of protein synthesis, global responses in bacteria and action of antibiotics.

Preface

A CHEMIST'S SURVEY OF DIFFERENT ANTIBIOTIC CLASSES
Introduction
Aminoglycosides
Beta-Lactams
Linear Peptides
Cyclic Peptides
Thiazolylpeptides
Macrolactones
Ansamycins-Rifamycins
Tetracyclines
Oxazolidinones
Lincosamides
Pleuromutilins
Quinolones
Aminocoumarins

ANTIBACTERIAL DISCOVERY: PROBLEMS AND POSSIBILITIES
Introduction
Why Is Antibacterial Discovery Difficult? The Problems
Target Choice: Essentiality
Target Choice: Resistance
Cell Entry
Screening Strategies
Natural Products
Computational Chemistry, Virtual Screening, Structure- and Fragment-Based Drug Design (SBDD and FBDD)
Conclusions

IMPACT OF MICROBIAL NATURAL PRODUCTS ON ANTIBACTERIAL DRUG DISCOVERY
Introduction
Natural Products for Drug Discovery
Microbial Natural Products
The Challenge of Finding Novel Antibiotics from New Natural Sources
Workflow for Drug Discovery from Microbial Natural Products
Antimicrobial Activities: Targets for Screens
Natural Products: A Continuing Source for Inspiration
Genome Mining in Natural Product Discovery
Conclusions

ANTIBIOTICS AND RESISTANCE: A FATAL ATTRACTION
To Be or Not To Be Resistant: Why and How Antibiotic Resistance Mechanisms Develop and Spread among Bacteria
Bacterial Resistance to Antibiotics by Enzymatic Degradation or Modification
Antibiotic Target Alteration: The Trick Exists and It Is in the Genetics
Efflux Systems
The Case Stories of Intrinsic and Acquired Resistances
Strategies to Overcome Resistance

FITNESS COSTS OF ANTIBIOTIC RESISTANCE
Introduction
Methods to Estimate Fitness
Factors Affecting Fitness
Mechanisms and Dynamics Causing Persistence of Chromosomal and Plasmid-Borne Resistance Determinants

INHIBITORS OF CELL-WALL SYNTHESIS
Introduction
MraY Inhibitors
Lipid II Targeting Compounds
Bactoprenol Phosphate
Conclusions

INHIBITORS OF BACTERIAL CELL PARTITIONING
Introduction
Bacterial Cell Division
Cell Division Proteins as Therapeutic Targets
Status of FtsZ-Targeting Compounds: From Laboratory to Clinic
Conclusion

THE MEMBRANE AS A NOVEL TARGET SITE FOR ANTIBIOTICS TO KILL PERSISTING BACTERIAL PATHOGENS
Introduction
The Challenge of Treating Dormant Infections
Discovery Strategies to Prevent or Kill Dormant Bacteria
Why Targeting the Membrane Could Be a Suitable Strategy
Target Essentiality and Selectivity
Multiple Modes of Actions
Therapeutic Use of Membrane-Damaging Agents against Biofilms
New Approaches to Identifying Compounds That Kill Dormant Bacteria
Challenges for Biofilm Control with Membrane-Active Agents
Potential for Membrane-Damaging Agents in TB Disease
Application to Treatment for Clostridium difficile Infection
Is Inhibition of Fatty Acid/Phospholipid Biosynthesis Also an Approach?
Concluding Remarks

BACTERIAL MEMBRANE, A KEY FOR CONTROLLING DRUG INFLUX AND EFFLUX
Introduction
The Mechanical Barrier
Circumventing the Bacterial Membrane Barrier
Conclusion

INTERFERENCE WITH BACTERIAL CELL-TO-CELL CHEMICAL SIGNALING IN DEVELOPMENT OF NEW ANTI-INFECTIVES
Introduction
Two-Component Systems (TCSs) as Potential Anti-Infective Targets
WalK/WalR and MtrB/MtrA: Case Studies of Essential TCSs as Drug Targets
Targeting Nonessential TCS
Non-TCSs Targeting Biofilm Formation and Quorum Sensing in Pseudomonas spp.
Conclusions

RECENT DEVELOPMENTS IN INHIBITORS OF BACTERIAL TYPE IIA TOPOISOMERASES
Introduction
DNA-Gate Inhibitors
ATPase-Domain Inhibitors
Simocyclinones, Gyramides, and Other Miscellaneous Inhibitors
Conclusions and Perspectives

ANTIBIOTICS TARGETING BACTERIAL RNA POLYMERASE
Introduction
Antibiotics Blocking Nascent RNA Extension
Antibiotics Targeting RNAP Active Center
Antibiotics Blocking Promoter Complex Formation
Inhibitors Hindering Sigma-Core Interactions
Inhibitors with Unknown Mechanisms and Binding Sites
Conclusions and Perspectives

INHIBITORS TARGETING RIBOSWITCHES AND RIBOZYMES
Introduction
Riboswitches as Antibacterial Drug Targets
Ribozymes as Antibacterial Drug Targets
Concluding Remarks and Future Perspectives

TARGETING RIBONUCLEASE P
Introduction
Targeting