Emerging role of biologics for the treatment of melioidosis and glanders

ABSTRACT

Introduction: Two important pathogenic species within the genus Burkholderia, namely Burkholderia pseudomallei (Bpm) and Burkholderia mallei (Bm), are the causative agents of the life-threatening diseases melioidosis and glanders, respectively. Due to their high mortality rate and potential for aerosolization, they have gained interest as potential biothreat agents and are classified as Tier 1 Select Agents.

Areas covered: The manuscript provides an overview of the literature covering the efforts taken in the last 10 years to develop new therapeutics measures against both Bpm and Bm, with attention on novel therapeutic agents.

Expert Opinion: As a result of the complicated antibiotic regimens necessary to treat these infections, development of novel therapeutics is needed to treat both diseases. In recent years, the understanding of the pathogenesis of Burkholderia has improved significantly and so have the efforts to develop novel therapeutic agents with high efficacy, either alone, or in combination with conventional antibiotics.

KEYWORDS:

• Burkholderia mallei
• Burkholderia pseudomallei
• melioidosis
• glanders
• antibiotics
• phages
• antibodies
• vaccines
• therapeutics

Article Highlights

• B. pseudomallei (Bpm) and B. mallei (Bm) are genetically related pathogens (>99% sequence homology) with similar pathogenic mechanisms and limited treatment options.

• Mixed antibiotic treatments for prolonged time periods are currently required to treat melioidosis and glanders, but they are partially effective.

• The guidelines for the treatment of melioidosis include intensive (10 – 14 days) intravenous therapy including ceftazidime or meropenem, followed by an extensive (3 – 6 months) oral eradication phase therapy including trimethoprim-sulfamethoxazole.

• Though the combination of antimicrobial compounds has shown the most significant progress in the ability to target Bpm or Bm, few studies have assessed the potential of compounds to target disease relapse or the ability to eradicate persistent infections.

• The increased understanding of Bpm and Bm pathogenesis has led to the identification of novel promising candidates including a FabI enoyl-ACP reductase inhibitor (PT01 and PT52), as well as protein synthesis inhibitors including, BAL30072 and 1950 against Bpm and Bm, respectively.

• CpG remains a widely studied immune modulator for the treatment and prevention of Bpm in small animal models with some promising results, this compound could also provide excellent adjuvant-like properties that could strengthen a wide range of vaccine platforms.

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Declaration of interest

The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was funded by NIH NIAID grant AI12660101 awarded to AG Torres. DT was funded by an NIH NIAID Research Supplement for Underrepresented Minorities (AI126601-02S1). DT was further supported by the UTMB Sealy Institute for Vaccine Science Pre-Doctoral fellowship.