New design method could create antibiotics that won't harm hearing

Disease-causing bacteria have long instigated a racket in the scientific community as researchers scrambled to oppose ever-resistant strains of tuberculosis and other infections of comparable pedigree with formidable antibiotic defiance.

To date, many of the antibiotics produced in the midst of such circumstances have required their takers pay a hefty toll — hearing loss in exchange for being infection-free. But new research conducted by a triumvirate of biological and medical research institutions has yielded a novel technique by which powerful antibiotics can be fashioned to fight infection without invoking hearing detriment.

A researching pool comprised of experts from Switzerland, England and the University of Michigan have outlined in their paper, recently published in the Proceedings of the National Academy of Sciences, how apramycin — an antibiotic commonly used in veterinary medicine — aligns with their proposed testing-platform for antibiotic design. And although apramycin has yet to be tested in humans, it meets the criteria of eliminating infection without damaging the sensory cells of the inner ear.

One of the study’s authors, Jochen Schacht, PhD, a professor of biological chemistry and otolaryngology and director of the Kresge Hearing Research Institute at the U-M Medical School, noted the unexpectedness of arriving at apramycin in the “theory-based approach to the synthesis of new effective aminoglycosides”:

“We were not surprised that some of our initial compounds (still under development) were effective and had low ototoxicity,” he said. “We were surprised, though, that an existing but clinically overlooked aminoglycoside fit the theoretical mold and proved to be what we were looking for, particularly as a drug against multidrug-resistant bacteria.”

Research for the paper was spurred by setbacks present in the current crop of aminoglycoside antibiotics, including kanamycin, gentamicin and amikacin. This drug subset has been known to cause hearing loss in 20 percent of patients who take them for a brief period of time, while longer timeframes of use, months or years, affect hearing adversely in 100 percent of patients taking the antibiotics. Patients with the infrequent mitochondrial “1555 mutation,” which packs an inherent predisposition to hearing loss, could become deaf following one administered dose of an aminoglycoside. Such ototoxicity has been a severe deterrent for the prescribing of aminoglycosides by physicians, Schacht said. 

“When [aminoglycoside antibiotics] were discovered in the 1940s, they were hailed as the silver bullet against infections (and tuberculosis in particular), but then were seen to have severe side effects. Need for them nevertheless mandated their use. In the 80s and 90s obituaries were written for them because of the development of cephalosporins and similar antibiotics. Now we find them still indispensable: acute infections, cystic fibrosis, leishmaniasis, multidrug-resistant tuberculosis.”

The paper’s rational approach to designing antibiotics that will achieve both aims of halting infection while simultaneously preserving a person’s hearing is based upon the more explicit targeting of bacterial ribosomes over mitochondrial ribosomes. While this theoretical framework could do little to effectuate attitude shifts, Schacht believes the practical results should cause prescribers and developers of the drugs to think again, as “aminoglycosides with no or low ototoxicity would fill an important niche.”

With about 440,000 new cases of multidrug-resistant tuberculosis occurring annually (150,000 of which result in death worldwide, according to the World Health Organization) pursuing promising aminoglycosides with low ototoxicity like apramycin is required if the industry wishes to not only save lives, but preserve one key human sense, researchers argue. Contributors to the paper — including teams headed by University of Zurich microbiologist Erik Bottger, and Nobel Prize winning structural biologist Venkatraman Ramakrishnan of England's Medical Research Council Laboratory of Molecular Biology, scientists from ETH Zurich, as well as Schacht’s U-M cohorts — are eager to launch clinical trials on apramycin if they can get the financing.

“Sooner or later (hopefully sooner than later) we will have much-needed broad-spectrum antibiotics available that solve the current problems of “superbugs” including multi-drug resistant tuberculosis,” Schacht said. “Or help against the pulmonary infections in cystic fibrosis patients without jeopardizing their hearing or balance.”

Schacht shared one final important factor contributing to the study’s success in his concluding remarks: “The study is also as an example of effective international teamwork — teamwork being essential to address complex questions.”

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