Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Round up.

By Wai Lang Chu

- Last updated on GMT

Related tags: Staphylococcus aureus

The latest research included in the proceedings of the Interscience
Conference on Antimicrobial Agents and Chemotherapy (ICAAC) means
that antibiotic treatments and management therapies feature
strongly in DrugResearcher’s round-up of the 4-day event.

The gathering is a chance for scientists and cancer researchers, as well as pharmaceutical and biotechnology companies from around the world to present the latest in scientific research to the attending microbiological community.

The meeting, which is taking place in Washington DC, was used to present data from Elusys Therapeutics, which described results of two preclinical studies of ETI-211, the Company's Heteropolymer (HP) antibody drug candidate targeting methicillin-resistant Staphylococcus aureus (MRSA) infections.

MRSA is a type of bacteria that is resistant to almost all antibiotics. These antibiotics include methicillin and other more common antibiotics such as oxacillin, penicillin and amoxicillin. S. aureus infections, including MRSA, occur most frequently among persons in hospitals and healthcare facilities (such as nursing homes and dialysis centres) who have weakened immune systems.

In the study, "A Heteropolymer directed against Staphylococcal Protein A prevents spread of blood-borne S. aureus to organs," Elusys scientists studied S. aureus distribution and clearance in ETI-211 treated mice.

Four days after S. aureus infection, kidney, liver and spleens from animals pre-treated with ETI-211 showed no evidence of live bacteria whereas organs from control animals showed high bacteria count.

This data demonstrated the ability of HP antibodies to remove infectious agents from the bloodstream and deliver them to the liver where they are destroyed by liver macrophages.

"The ETI-211 data presented today highlight the unprecedented efficacy of this Heteropolymer antibody product to clear methicillin-resistant S. aureus infections and provide a 'vaccine-like' immune protection against subsequent infection,"​ said Elizabeth Posillico, president and chief executive officer of Elusys Therapeutics.

A second study entitled, "A novel vaccination approach using an antibody conjugate targeting Staphylococcus aureus,"​ mice prophylactically treated with ETI-211 that survived an initial lethal MRSA challenge were subjected to a second lethal challenge of either MRSA or S. epidermidis (1 - 3 months later) with no additional drug treatment.

All animals initially treated with ETI-211 survived the second infection while all controls died. This broad "vaccine-like" protection was found to be due, at least in large part, to the production of significant levels of antibodies that recognise S. aureus, and S. epidermidis, as a result of ETI-211 clearance of S. aureus bacteria during the first infection.

Sangamo BioSciences, announced that data from its program to develop a ZFP Therapeutic for HIV/AIDS represented the first demonstration that cells can be made resistant to HIV infection by treatment with Sangamo's zinc finger DNA-binding protein nucleases (ZFN) designed to disrupt the CCR5 gene.

CCR5 is the chemokine receptor that HIV uses as a coreceptor to gain entry into immune cells.

CCR5 is perhaps the most important of the known coreceptors for HIV, since the most commonly transmitted strains of HIV are strains that bind to CCR5 - so-called "R5" strains.

A small fraction of the population carries a mutation in their CCR5 gene, called the delta32 mutation. This mutated version of the gene produces malformed CCR5 proteins, which cannot be used by HIV as a coreceptor.

Individuals that have mutant delta 32 versions of both of their CCR5 genes are resistant to infection by R5 HIV strains.

In its anti-HIV preclinical research program, Sangamo has designed ZFNs that can be used to disrupt the CCR5 gene, a receptor required for HIV entry into immune cells.

The researchers found that ZFN-modified cells were resistant to HIV infection whereas control cells were infected when challenged with the virus.

Furthermore, when CCR5 expression was experimentally restored in the ZFN-modified cells, HIV was once again able to infect these cells.

Sangamo has shown disruption of the CCR5 gene in a number of different cell types including T-cells, the target cell for this therapeutic approach.

"CCR5 is an important target in the fight against HIV/AIDS,"​ said Edward Lanphier, Sangamo's president and CEO. "Individuals with a natural mutation of their CCR5 gene have been shown to be resistant to HIV infection."

Several major pharmaceutical companies have initiated programs to develop small molecule drugs to block HIV binding to CCR5, but in recent months two trials have been halted, one due to reports of liver toxicity of the candidate drug.

Small molecule or antibody approaches require the constant presence of antagonist in high enough concentrations to block therapeutically relevant numbers of the CCR5 protein, of which there are approximately 10,000 copies on the surface of each T-cell.

"By administering ZFNs to patients, we could potentially provide HIV-infected individuals with a reservoir of healthy and uninfectable T-cells that would be available to fight both opportunistic infections and HIV itself,"​ said Dale Ando, Sangamo's vice president of therapeutic development and chief medical officer.

Rib-X Pharmaceuticals, announced that it had initiated Phase I trials of its first candidate for treating resistant infections.

The candidate had been derived from the company's Rx-01 program, which utilises X-ray crystallography and computational chemistry to facilitate drug design.

Rx-01 antibiotics are inhibitors of the ribosome, a complex cellular machine that catalyses the chemical steps to produce proteins.

The ribosome is composed of 2 complex subunits called the 30S and 50S ribosomal subunits. Rx-01 compounds bind to the larger 50S subunit.

Many existing classes of antibiotics, including those used to treat both community- and hospital-acquired infections, are known to function by targeting the 50S.

Among the classes of antibiotics that act this way are macrolides, ketolides and the oxazolidinones that contribute more than $3 billion to the annual antibiotic marketplace. Zithromax and Zyvox are examples of two such antibiotics.

Compounds from the Rx-01 program have been found to be active against multidrug-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA) and the newest emerging threat of Zyvox-resistant enterococci.

"Rib-X studies presented at ICAAC​ this year affirm that we have made substantial progress toward our goal of designing new and potent antibiotics that overcome resistance and expand the armamentarium against specific bacterial infections regarded as public health threats,"​ said Susan Froshauer, president and chief executive officer of Rib-X.

"A highly detailed knowledge of both the atomic structure of the ribosome, and our understanding of how this structure interacts with commercially available antibiotics, were essential to this progress."

Finally, Targanta Therapeutics presented three posters at the conference one of which detailed a new class of small molecule RNA Polymerase inhibitors that showed activity against Staphylococcus aureus.

Investigators identified a key member of this class, 2 ureidothiophene-3-carboxylate ester that has been shown to selectively inhibit transcription.

Additionally, they were able to demonstrate the effectiveness of the compound in a mouse model of S. aureus infection when administered parenterally.

The researchers said that more research was needed to further their development into useful therapies that will overcome the issue of resistance.

Mutating bacteria have become resistant to many existing antibiotics, making infections increasingly difficult to treat and creating a serious public health challenge.

Staphylococcus aureus (staph), a bacterium that can lead to infections in the heart, bones, lungs and bloodstream, often proves fatal.

According to the Centres for Disease Control and Prevention, over the last 30 years the percentage of staph bacteria resistant to traditional antibiotics rose by more than 50 per cent in US hospitals.

New antibiotics to treat drug-resistant bacterial strains could significantly increase the survival rate among patients with bacterial infections.

Related topics: Preclinical Research

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