Saturday, 8 April 2017

Bio-Conjugates: Upcoming Therapeutic Platform Against Bacterial Infections

The key powers of both antibody and antibiotic in a single conjugate molecule used against bacterial infection.

By Ratneshwar Thakur

In 2015, Sophie M. Lehar et al; reported in the journal “Nature”, their new antibody-antibiotic conjugate (AAC) killed Staphylococcus aureus in mice that frontline antibiotics like vancomycin failed to kill. Such treatment works by loading antibiotics onto antibodies with the help of linker which delivers a lethal dose of drug directly to the site of infection. An antibody is a protein used by the immune system to recognize and neutralize pathogens such as bacteria and viruses. Antibiotics are powerful medicines that fight bacterial infections.

Developments of these newer types of interventions are of utmost importance as many common infections, with the passage of time, are becoming resistant to antibiotics worldwide. At the same time, not many novel antibiotics or therapeutics have been developed for clinical use because of poor pharmacokinetic properties or toxicities.

Many antibiotics have potential to kill the variety of microorganisms and they are known as broad-spectrum antibiotics. But such antibiotics can also kill body’s good bacteria in our gut and intestine, which can lead to serious health risks. On one hand, as AAC, broad spectrum antibiotics might be used for targeted antimicrobial therapies to kill the harmful bacteria. On the other hand, many antibodies might become more useful in AAC, because, in spite of having exquisite specificity for the microbial target, they have not been successful as therapy in the clinic.

The concept of AAC is a variant of the antibody–drug conjugate (ADC) model that has been applied successfully to cancer treatment. In the case of cancer treatment, ADC uses the antibody to selectively deliver potent cytotoxic payloads to antigen-expressing tumor cells, whereas the AAC uses the antibody to deliver an antibiotic payload to bacteria. The AAC design has three building blocks: antibiotic payload to kill bacteria, an antibody to target the delivery of the payload to the bacteria, and a linker to attach the payload to the antibody. 

Sophie M. Lehar et al reported that many intracellular pathogens like S. aureus residing within host cells are protected from attack by extracellular host defenses. To escape the antibiotic therapy, these pathogens also become intrinsically resistant by adopting the semi-dormant state. The AAC therapeutic provides the possibility to specifically tag and kill pathogens like S. aureus because they periodically escape from their intracellular niches. The direct delivery of a high concentration of antibiotic by AAC at the site of infection can eliminate the harmful bacteria that are not effectively eliminated by traditional antibiotic treatment. 

For many reasons, scientists believe that the key powers of both antibody and antibiotic in a single conjugate molecule have the potential to be expanded to other hard-to-treat bacterial infections such as tuberculosis. First, the therapeutic index can be improved by maximizing efficacy and minimizing off-target toxicity. Second, due to the antibody specificity, the AAC has potential to transform a broad-spectrum antibiotic into a pathogen-specific antibiotic. Third, a potential use of a linker might be to release a high local concentration of active antibiotic at the target. 

AAC approach is very promising, as it has robust potential to cut the emergence of antibiotic resistance by reducing exposure of other bacteria to the active drug. Future developments of bio-conjugates should focus on technologies that permit the attachment of more antibiotics per antibody without affecting the pharmacokinetic properties of the AAC. Also, to limit the damage of body's beneficial microbes, it is important to design an efficacious AAC by developing advanced conjugation strategies to maximize specific binding, internalization, and payload release at the site of infection.

Here is a link to published article:

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