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Chemical Strategies to Target Bacterial Virulence

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Chemical Strategies to Target Bacterial Virulence Review pubs.acs.org/CR Chemical Strategies To Target Bacterial Virulence † ‡ ‡ † ‡ § ∥ Megan Garland, , Sebastian Loscher, and Matthew Bogyo*, , , , † ‡ § ∥ Cancer Biology Program, Department of Pathology, Department of Microbiology and Immunology, and Department of Chemical and Systems Biology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, United States ABSTRACT: Antibiotic resistance is a significant emerging health threat. Exacerbating this problem is the overprescription of antibiotics as well as a lack of development of new antibacterial agents. A paradigm shift toward the development of nonantibiotic agents that target the virulence factors of bacterial pathogens is one way to begin to address the issue of resistance. Of particular interest are compounds targeting bacterial AB toxins that have the potential to protect against toxin-induced pathology without harming healthy commensal microbial flora. Development of successful antitoxin agents would likely decrease the use of antibiotics, thereby reducing selective pressure that leads to antibiotic resistance mutations. In addition, antitoxin agents are not only promising for therapeutic applications, but also can be used as tools for the continued study of bacterial pathogenesis. In this review, we discuss the growing number of examples of chemical entities designed to target exotoxin virulence factors from important human bacterial pathogens. CONTENTS 3.5.1. C. diphtheriae: General Antitoxin Strat- egies 4435 1. Introduction 4423 3.6. Pseudomonas aeruginosa 4435 2. How Do Bacterial AB Toxins Work? 4424 3.6.1. P. aeruginosa: Inhibitors of ADP Ribosyl- 3. Small-Molecule Antivirulence Agents 4426 transferase Activity 4435 3.1. Clostridium difficile 4426 3.7. Bordetella pertussis 4436 3.1.1. C. difficile: Ion-Exchange Resins 4427 3.7.1. B. pertussis: Inhibitors of Adenylyl 3.1.2. C. difficile: Inhibitors of the Cysteine Cyclase Activity 4436 Protease Domain 4428 3.8. Bacillus anthracis 4436 3.1.3. C. difficile: Inhibitors of the Glucosyl- 3.8.1. B. anthracis: Inhibitors of Toxin Assem- transferase Domain 4429 bly 4437 3.1.4. C. difficile: General Antitoxin Strategies 4429 3.8.2. B. anthracis: Inhibitors of Toxin Internal- 3.2. Clostridium sordellii 4430 ization 4438 3.2.1. C. sordellii: Inhibitors of the Glucosyl- 3.8.3. B. anthracis: Inhibitors of Adenylyl transferase Domain 4430 Cyclase Activity 4439 3.3. Vibrio cholerae 4430 3.8.4. B. anthracis: Inhibitors of the Metal- 3.3.1. V. cholerae: Inhibitors of Toxin Tran- loprotease Domain 4440 scription 4432 3.9. Clostridium botulinum 4443 3.3.2. V. cholerae: Inhibitors of Toxin Assembly 4432 3.9.1. C. botulinum: Inhibitors of the Metal- 3.3.3. V. cholerae: Host Cell Receptor Mimics 4432 loprotease Domain of BoNT B 4443 3.3.4. V. cholerae: Inhibitors of Toxin Internal- 3.9.2. C. botulinum: Inhibitors of BoNT A 4443 ization 4432 3.10. Clostridium tetani 4446 3.3.5. V. cholerae: Inhibitors of ADP Ribosyl- 3.10.1. C. tetani: Inhibitors of Toxin Internal- transferase Activity 4433 ization 4447 3.3.6. V. cholerae: Natural Product Inhibitors of 3.10.2. C. tetani: Inhibitors of the Metal- Toxin Function 4433 loprotease Domain 4447 3.3.7. V. cholerae: Inhibitors of the Cysteine 3.11. Shigella dysenteriae Type 1 and Shiga Toxin Protease Domain 4433 Producing E. coli (STEC) 4447 3.4. Enterotoxigenic Escherichia coli 4434 3.11.1. S. dysenteriae and STEC: Inhibitors of 3.4.1. Enterotoxigenic E. coli: Inhibitors of Stx and Stx1 4448 Toxin Assembly 4434 3.11.2. STEC: Inhibitors of Stx2 4451 3.4.2. Enterotoxigenic E. coli: Host Cell Re- ceptor Mimics 4435 3.5. Cornybacterium diphtheriae 4435 Received: October 3, 2016 Published: February 24, 2017 © 2017 American Chemical Society 4422 DOI: 10.1021/acs.chemrev.6b00676 Chem. Rev. 2017, 117, 4422−4461 Chemical Reviews Review 4. Conclusions and Future Directions 4451 mutations that render these compounds less active or inactive. Author Information 4453 Resistance through evolution, therefore, is a continuous process Corresponding Author 4453 and must be countered with judicious use of the currently ORCID 4453 effective antibiotics, as well as continued development of novel Notes 4453 therapeutics. Biographies 4453 Another contributing factor to the rise in resistance is the List of Abbreviations 4453 overuse of antibiotics. To begin to address this issue, the White References 4454 House announced a National Action Plan for Combating Antibiotic-resistant Bacteria in 2015, with a goal to reduce overuse of antibiotics by 50% in the outpatient setting, and by 1. INTRODUCTION 20% in the inpatient setting, by 2020.16 Globally, the World Antibiotic resistance is a growing problem that now causes Health Organization (WHO) formed a global action plan, 700 000 deaths per year worldwide.1,2 In the 1930s, the advent calling on all countries to increase awareness and knowledge of highly effective antibiotics rendered previously fatal bacterial surrounding antibiotic use, to improve preventative measures, infections minor inconveniences. Bayer’s development of sulfa to optimize the use of antibiotics in human and animal health, drugs3 and Alexander Fleming’s discovery of penicillin from the and to incentivize investment in novel interventions such as 17 fungus Penicillium chrysogenum4 spurred the development of medicines and diagnostics. While the exact number of additional classes of antimicrobials that have added to our inappropriate antibiotic prescriptions is unknown, a recent arsenal of therapies to keep infectious diseases in check.5 At the study suggested that, of the estimated 154 million annual same time, however, once-susceptible microbes have gained prescriptions for oral antibiotics in the ambulatory care setting resistance to the antibiotics that used to be viable treatment in the United States, 30% of these prescriptions were 18 options. Today, antibiotic resistance is a serious and complex inappropriate. These numbers alone are striking, and the global health issue that threatens to undermine the significant analysis did not include hospitalized patients. Therefore, the scientific and medical progress made over the past 80 years to absolute number of inappropriately prescribed antibiotics is combat infectious diseases. The increase in antibiotic resistance certainly higher. Adequate antibiotic stewardship also requires is a multifactorial problem stemming from evolution by the determination of the correct drug and dose to use when bacterium, overuse and misuse of antibiotics, as well as a medically indicated, as well as calls upon patients to take decrease in production of new antimicrobial agents with novel prescriptions as indicated. Engaging patients in these efforts to mechanisms of action. In 2013, the Centers for Disease Control minimize the emergence of resistance will require increased and Prevention (CDC) recognized 17 bacteria (and one education and awareness about the cause of bacterial resistance. fungus) as threats to society, stratifying them based on their Recent studies conducted by the Wellcome Trust and the antibiotic resistance and severity of the threat (Table 1).6 WHO found that many people erroneously believe that patients The growing problem of bacterial resistance can be become resistant to antibiotics, rather than the bacteria 1,2,19 exemplified by the recent reports of “superbugs” in the acquiring resistant genes. This may lead to misuse of mainstream media. The first known case of Escherichia coli antibiotics, with patients believing that they should stop the harboring the mcr-1 plasmid containing resistance genes for the course of treatment as soon as they feel better to decrease their antibiotic colistin was recently cultured from a woman with a likelihood of developing resistance to the treatment. urinary tract infection (UTI) in Pennsylvania.7 The mcr-1 Finally, lack of development of novel antibiotics is another plasmid was first reported in livestock in China, and has since contributing factor that limits our arsenal of drugs to treat − spread across many continents.7 9 Colistin is an antibiotic infections as they become resistant to other antibiotics. While belonging to the polymyxin class that was introduced in the resistance is on the rise, pharmaceutical companies have 1950s and eventually fell out of favor due to severe side decreased their antimicrobial programs, with United States effects.10 Today, it is typically thought of as a last resort therapy Food and Drug Administration (FDA) approval of antibiotics for multidrug-resistant (MDR) gram-negative bacteria, and decreasing 56% in the 5-year period of 1998−2002 compared resistance to this antibiotic is rare.10 Therefore, the discovery of to 1983−1987.20 This decline is largely due to lack of the mcr-1 plasmid, which allows horizontal transfer of colistin incentives, as the high costs of developing a new therapy are resistance genes, is troubling as it has the potential to open the less likely to be recouped by an antibiotic with a short-term door for truly pan-resistant microbes. With recent reports of course of treatment.21 In response to this, the Generating three more cases of bacteria bearing the mcr-1 plasmid cultured Antibiotic Incentives Now (GAIN) Act was signed into law in from patients in the United States,9,11,12 resistance to colistin is July 2012, giving qualified antibiotics an expedited review a growing concern. Another recent outbreak of MDR bacteria process and a greater number of years of exclusivity on the occurred in California hospitals in association
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