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Novel Antimicrobials for Killing Anthrax

The CDC’s Division of High-Consequence Pathogens and Pathology (DHCPP) Bacterial and Special Pathogens Branch this week announced its intent to issue a purchase order to the University of Michigan Life Sciences Institute for the production of novel antimicrobials for specific killing of Bacillus anthracis.

Despite the problem of bacteria becoming increasingly resistant to the current arsenal of therapeutic agents, few novel classes of antimicrobials have been discovered.  In addition to naturally acquired resistance, there is increasing concern that engineered, multi-drug resistant (MDR) strains could be used in a bioterrorism event.  According to the CDC, such an occurrence could greatly limit or eliminate their ability to effectively treat diseases such as anthrax, where early administration of appropriate antimicrobials is critical for care and a positive patient outcome.

One approach in recent years has been to use anti-sense oligonucleotides (oligos) to target specific mRNA to inhibit bacterial growth. Although the anti-sense approach has been used since the 1970s, several developments have led to more recent success. First was the development of morpholino oligos, which are resistant to ribonucleases, and thus more stable. Second was the addition of membrane-penetrating peptides to morpholino oligos in order to increase uptake and effectively kill bacteria.

The planned effort involves using morpholino oligos linked to Bacillus anthracis siderophores to treat anthrax. The siderophores bind iron and the iron-siderophore complex is then transported across the cell envelope into the cell. The siderophore would act as a “Trojan horse” and lead to the active uptake of the drug, and approach that has been used successfully with traditional antibiotics.

Work to generate a new class of antimicrobial agents will focus on generating a modified form of the virulence factor petrobactin that is covalently modified with an anti-sense morpholino oligonucleotide. The process requires the development of a method to conjugate a morpholino-oligonucleotide to the siderophore. This molecule would be recognized by receptors on the cell surface of the bacteria, and internalized where the covalently linked antisense oligonucleotide would bind to its complimentary strand of RNA blocking translation of genes necessary for growth.

Such a process could be applied as a means of killing other pathogenic bacteria and used as a therapeutic in the case of organisms with resistance to currently used antibiotics.

The contract effort is managed under Solicitation Number: 00HCVLEG-2012-43251.

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