Drug Discovery Targeting Drug-Resistant Bacteria

Prashant Kesharwani, Sidharth Chopra, Arunava Dasgupta

• Publisher: Academic Press
• Year: 2020
• ISBN:
  9780128184813
• Topic: Medicine
• Subtopic: Pharmacology

Drug Discovery Targeting Drug-Resistant Bacteria explores the status and possible future of developments in fighting drug-resistant bacteria. The book covers the majority of microbial diseases and the drugs targeting them. In addition, it discusses the potential targeting strategies and innovative approaches to address drug resistance. It brings together academic and industrial experts working on discovering and developing drugs targeting drug-resistant (DR) bacterial pathogens. New drugs active against drug-resistant pathogens are discussed, along with new strategies being used to discover molecules acting via new modes of action. In addition, alternative therapies such as peptides and phages are included.

Pharmaceutical scientists, microbiologists, medical professionals, pathologists, researchers in the field of drug discovery, infectious diseases and microbial drug discovery both in academia and in industrial settings will find this book helpful.

• Written by scientists with extensive industrial experience in drug discovery
• Provides a balanced view of the field, including its challenges and future directions
• Includes a special chapter on the identification and development of drugs against pathogens which exhibit the potential to be used as weapons of war

Foreword 1

Our history with antibiotics is remarkably short. In 1906, Paul Ehrlich developed Compound 606 or Arsphenamine, the first chemotherapeutic agent that was able to selectively attack a bacterial organism (spirochetes, which causes syphilis). However, the modern age of antibiotics that were safe to humans but able to kill bacteria at the site of infection goes back only to 1928 with the discovery of penicillin. In fact, the first person to be treated with an antibiotic was as recent as 1942, within current living memory. Nevertheless, resistance has arisen to most antibiotics soon after they were introduced into clinical practice. But that is not unexpected. As many antibiotics are derived from naturally occurring compounds that are derived from fungi, it is but natural that the genetic basis for resistance is present in a small proportion of bacteria. The massive selection pressure we have applied on these “resistant” strains of bacteria through the use of millions of tons of antibiotics, in humans, animals, and the environment, has ensured that resistance is no longer a rare phenomenon. Indeed, in the case of many bacteria pathogens, a significant proportion of bacteria causing infections no longer respond to antibiotics.

Antimicrobial resistance (AMR) has been compared to climate change. Resistance can emerge in any part of the world because of antibiotic overuse or misuse and the rapid dissemination of resistant pathogens globally. There are 10 million people on an airplane on any given day and bacteria do not need passports or visas to move around the world. Like with climate change, individuals and countries are not fully incentivized to tackle the AMR problem on their own. However, there is one important respect in which AMR is not like climate change. The potential for drug resistance was known even before penicillin was used on a single patient, unlike with climate change, where the impact on climate was not understood at the dawn of the fossil fuel age.

Alexander Fleming warned of drug resistance in his Nobel Lecture in 1945, “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.” Despite these early warnings, we have failed to ensure that penicillin and other antibiotics are not bought by anyone without medical knowledge. And we have seen the consequences.

In this book “Antibiotics: Past, present and future,” the editors Prashant Kesharwani, Arunava Dasgupta, and Sidharth Chopra have put together a remarkable compendium of papers addressing various aspects of the AMR challenge. AMR is global, and it is but natural that science to address the problem of resistance including on discovery of new antimicrobial agents should also be global. India, as the world’s large consumer of antibiotics for use in humans, and as a country with a challenged public health and sanitation system, is bearing the brunt of the AMR burden. It is timely that researchers in India have enthusiastically taken up the scientific challenge of tackling AMR.

There may come a time when we are no longer dependent on antibiotics because of advances in science that we cannot yet see. Perhaps phage therapies, vaccines, monoclonal antibodies, and probiotics would have advanced to a stage where our reliance on antibiotics is much diminished. But until that time, we owe it to future generations to ensure that they do not enter a world where antibiotics no longer work, for no fault of their own.

Ramanan Laxminarayan

Foreword 2

Antimicrobial Resistance (AMR) is one of the biggest challenges the world faces today. The issue is as complex as global warming and global poverty, requiring coordinated efforts of all stakeholders, including the medical community, scientists, policymakers, pharmaceutical industry, politicians, and the public. One of the basic reasons for the current AMR scenario is the dry anti-infective pipeline. The reasons behind this dry pipeline are well known.

The book “Drug Discovery Targeting Drug-Resistant Bacteria” is very comprehensive, with an introductory chapter on why there is an urgent need for newer anti- infectives, and multiple well-written sections covering very important aspects such as mechanisms of drug resistance, drugs targeting various groups of bacteria, newer approaches to drug discovery including peptides and a detailed discussion on the role of phages.

The monogram is an excellent resource that helps us to delve deep into the intricacies of the current AMR scenario and a souvenir on the light at the far end of the tunnel.

I congratulate Dr. Sidharth Chopra and team for their sincere effort on a topic of high public health significance.

Abdul Ghafur

Acknowledgments

We wish to sincerely thank the authors for offering to write comprehensive chapters on a tight schedule. This is generally an added responsibility in the hectic work schedules of researchers. We express our earnest gratitude to the reviewers, who provided their critical views for the improvement of the book chapters. We would also like to thank reviewers of our book proposal for their suggestions in the framing of the chapters. We also thank Timothy Bennett (Editorial Project Manager, Elsevier), whose efforts during the preparation of this book were very useful.

Editors

Chapter 1

Antibiotics: past, present, and future

Ritesh Thakare^a

Prashant Kesharwani^b

Arunava Dasgupta^a

Nanduri Srinivas^c

Sidharth Chopra^a
a Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
^b Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
^c Department of Medicinal Chemistry, NIPER-HYD, Hyderabad, India

Abstract

The discovery and development of antimicrobials is one of the miracles of modern science and has positively impacted human health care globally. Unfortunately, antibiotics became a victim of their own success and their often inappropriate and unrequited utilization lead to the unabiding nightmare known as antimicrobial resistance. In this chapter, the authors present the history and the future challenges associated with antibiotics, including various initiatives launched globally to counter the unrelenting threat to modern medicine.

Keywords: antibiotics

resistance

antimicrobial

drugs

magic bullet

1. Introduction

1.1. History and discovery of antimicrobials

Selman Waksman, one of the very first investigators in the field of antimicrobial chemotherapy and bacteriology, coined the term “antibiotic” [1]. The term was singularly used to refer to a molecule that was used against bacteria and exhibited bacteriostatic or bactericidal activity. However today, the term antibiotics or antimicrobials is often used interchangeably for compounds used in the treatment of bacterial, fungal, protozoan, or other microbial infections. As has been well documented, infectious diseases have a significant impact on human morbidity and mortality and have shaped human evolution and history. The discovery of antimicrobials is one of the most significant breakthroughs that revolutionized human medical sciences as antibiotics have saved millions of lives and increased life expectancy all across the globe.

Paul Ehrlich started the never-ending quest of discovery of antimicrobials along with Sahachiro Hata. They identified a compound, marketed as Salvarsan, that showed antibacterial activity against Treponema pallidum, the causative agent of syphilis that had a major impact on health care in 19th century Europe. The discovery of salvarsan gave the concept o...

Table of contents

• Cover
• Title page
• Contents
• Copyright
• Dedication
• Contributors
• Foreword 1
• Foreword 2
• Acknowledgments
• Chapter 1: Antibiotics: past, present, and future
• Chapter 2: Mechanisms of antibacterial drug resistance and approaches to overcome
• Chapter 3: Antibiotics targeting Gram-negative bacteria
• Chapter 4: Recent development of antibacterial agents to combat drug-resistant Gram-positive bacteria
• Chapter 5: Repurposing nonantibiotic drugs as antibacterials
• Chapter 6: Drugs against Mycobacterium tuberculosis
• Chapter 7: Combating biothreat pathogens: ongoing efforts for countermeasure development and unique challenges
• Chapter 8: New approaches to antibacterial drug discovery
• Chapter 9: New strategies and targets for antibacterial discovery
• Chapter 10: Importance of efflux pumps in subjugating antibiotic resistance
• Chapter 11: Phage therapy—bacteriophage and phage-derived products as anti-infective drugs
• Chapter 12: Drug discovery targeting drug-resistant nontuberculous mycobacteria
• Chapter 13: New strategies to combat drug resistance in bacteria
• Index