Antimicrobials for Bacterial Bioterrorism Agents

Mitali Sarkar-Tyson; Helen S Atkins

Future Microbiol. 2011;6(6):667-676.

Abstract and Introduction

Abstract

The limitations of current antimicrobials for highly virulent pathogens considered as potential bioterrorism agents drives the requirement for new antimicrobials that are suitable for use in populations in the event of a deliberate release. Strategies targeting bacterial virulence offer the potential for new countermeasures to combat bacterial bioterrorism agents, including those active against a broad spectrum of pathogens. Although early in the development of antivirulence approaches, inhibitors of bacterial type III secretion systems and cell division mechanisms show promise for the future.

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Cite this: Antimicrobials for Bacterial Bioterrorism Agents - Medscape - Jun 01, 2011.

Table 1. Key virulence determinants and inhibitors for bioterrorism agents.
Virulence mechanisms	Specificity	Characterization	Current status of inhibitor development
Secretion systems	Present in multiple agents	Mutations in TTSS genes results in attenuation in uptake and survival in cell culture models in vitro and in animal models of infection	Classes of inhibitors identified through HTS
Polysaccharide biosynthesis	Present in multiple agents	Mutagenesis of polysaccharide biosynthesis results in avirulent or attenuated pathogens. Polysaccharides can be species specific	No inhibitors identified
Adhesins	Present in multiple agents	Genetic mutagenesis has shown them to play a role in virulence for bioterrorism agents	No inhibitors identified
Toxins	Present in Bacillus anthracis; possibly in Burkholderia pseudomallei	Well-defined toxins in B. anthracis; suggested but as yet uncharacterized B. pseudomallei toxin	HTS in early stage
Metabolic enzymes	Present in multiple agents	Various genes involved in metabolic pathways are essential for agent; potential for human homologs	Inhibitor identification/development in early stage
Cell division	Present in multiple agents	No reported genetic mutagenesis studies	No inhibitors identified
Quorum sensing	Present in multiple agents	Shown to be important for growth and biofilm production in some agents	Inhibitors under evaluation

HTS: High throughput screens; TTSS: Type III secretion system.

Box 1. Issues associated with antimicrobials for bioterrorism agents.
Good animal models of disease are required since the traditional drug development route involving human clinical trials for antimicrobial efficacy is not usually possible Antimicrobials should be effective against inhalational infection with bioterrorism agents, the likely route of infection following an attack Antimicrobials should be stockpiled for widespread use in an event, so long storage life and low cost is essential Antimicrobials need to be easy to acquire and distribute for quick widespread use in an event, so stability at room temperature and ability to administer orally is preferable Antimicrobials for bioterrorism agents should be safe for use in the entire population – adults, children, pregnant women and immunosuppressed individuals

Box 2. CDC priority bacterial bioterrorism agents (diseases).
Category A Bacillus anthracis (anthrax) Francisella tularensis (tularemia) Yersinia pestis (plague) Category B Brucella species (brucellosis) Burkholderia mallei (glanders) Burkholderia pseudomallei (melioidosis) Chlamydia psittaci (Psittacosis) Coxiella burnetii (Q fever) Rickettsia prowazekii (typhus fever)

Box 3. Target selection criteria.
Genetic target validation using mutagenesis methods is required to determine essentiality of the target Recombinant protein expression is essential for protein characterization and for target assay development There should be little or, preferably, no homology to human proteins to ensure that antimicrobials are specific to pathogens Determination of the crystal structure is imperative for structure-based drug design Drug-like inhibitors should be known for the target, indicating a druggable active site

Sidebar

Executive Summary

Bioterrorism

Potential bacterial bioterrorism agents listed by the US CDC include Bacillus anthracis (anthrax), Francisella tularensis (tularemia), Yersinia pestis (plague), Burkholderia pseudomallei (melioidosis) and Burkholderia mallei (glanders).
The development of novel effective antimicrobials for bioterrorism agents presents particular challenges, including the requirement for good animal models of inhalational infection.
Antibiotics currently recommended for use in the event of bioterrorism include fluoroquinolones (particularly ciprofloxacin) and tetracyclines (particularly doxycycline).
Current antibiotics are believed to be effective for anthrax, plague and tularemia, although long regimens may be required and relapses may occur; current antibiotics are relatively ineffective for melioidosis and glanders.
Naturally occurring or engineered resistance to antibiotics is of significant concern.
Novel antimicrobials are needed for bioterrorism agents.

Antivirulence Strategy

The development of inhibitors to bacterial virulence factors offers a useful strategy for bioterrorism agents, including the potential for inhibitors of common targets for broad spectrum use.
Virulence-associated genes have been identified in bioterrorism agents by genome sequencing and comparison, microarray and proteomic technologies and random or directed mutagenesis approaches.
Inhibitors of protein targets in bacterial type III secretion systems and cell division machinery have been identified using high throughput screening, an approach which may be applied in the future to other identified targets.
Antivirulence inhibitor development is in its infancy but may offer an alternative approach to traditional antibiotics; in the future it may be possible to combat bioterrorism agents using antivirulence approach alone or in combination with other approaches.

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