New Approach to Tackling Multidrug-Resistant Bacteria

Scientists have identified a new strategy to generate novel antibiotics, according to the results of a new study published online September 27 in The FASEB Journal.

“These findings present an exciting new paradigm in antibiotic discovery using self-derived peptides that can be developed to target the structures of any essential bacterial proteins,” write co-lead authors, Dr. Jian Zhan and Dr. Husen Jia, both from Griffith University, Queensland, Australia, and colleagues.

“These peptides have been used to inhibit protein-protein interactions or to disrupt folded structures, but to date, they have not been used as antibiotics to specifically target the structures of essential bacterial proteins,” they add.

The emergence of multidrug-resistant (MDR) bacteria is a critical public health threat. And as this problem continues to spread, investigators continue to struggle to identify new antibiotics or alternative strategies to help combat the issue.

However, the high specificity and low toxicity risk of peptide-based drugs have highlighted them as desirable therapeutic agents, according to the authors. All living organisms produce antimicrobial peptides, they say, and these play a key role in the innate immune response.

Most antibiotics target superficial regions of key bacterial proteins. However, bacterial mutations can change these surface regions and lead to antibiotic resistance. To reduce the likelihood of bacteria developing antibiotic resistance, the investigators in this study targeted the deeper structural core of a bacterial protein.

To do this, the investigators used self-targeting, inhibitory peptides; these peptides are structure-disrupting and have a sequence derived from a region of the protein that it is designed to block.

They investigated KFF-EcH3, a helical peptide from an essential protein of the bacterium Escherichia coli. This peptide disrupted the structure of a key bacterial enzyme and killed the bacterium, including MDR strains. Importantly, the investigators did not detect any evidence to suggest that the bacterium developed resistance against KFF-EcH3 over 30 days.

Next, they used the same strategy to investigate the targeting of the same enzyme from Neisseria gonorrhoeae by a different structure-disrupting, self-derived peptide known as KFF-NgH1.

“This peptide inhibited bacterial growth and was able to treat a gonococcal infection in a human cervical epithelial cell model,” the authors write.

This study identifies a prototype of a novel class of antibiotic peptide derived from a region of an essential protein involved in structural core interactions, they emphasize.

And because each bacterium has hundreds of these essential proteins, the authors conclude that this strategy highlights an unused source for further studies to develop self-derived peptides to target the core structures of any essential bacterial proteins.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.