Newswise — Medical experts urgently require fresh antibiotics to combat drug-resistant bacteria. Scientists at the University of Zurich and Spexis, a company, have presently altered the chemical composition of naturally existing peptides to craft antimicrobial compounds that attach to unfamiliar components within the bacteria's metabolic process.
Every year, over five million individuals globally succumb to bacteria that exhibit resistance to the majority of conventional antibiotics. There is an urgent requirement for fresh antibiotics to guarantee the successful treatment of bacterial infections in patients. "Regrettably, the current pipeline for novel antibiotics is quite depleted," remarks Oliver Zerbe, a chemist and the director of NMR facilities at the University of Zurich. "It has been over five decades since the approval of antibiotics targeting previously unexplored molecular targets."
In a recent publication in Science Advances, Zerbe delves into the creation of an immensely potent category of antibiotics that combat Gram-negative bacteria using an innovative approach. The World Health Organization categorizes this bacterial group as exceptionally perilous. Within this group, which boasts a heightened resistance level owing to its dual cell membrane, reside carbapenem-resistant enterobacteria, among others. The study involved not only the UZH team but also researchers from the pharmaceutical company Spexis AG, as part of a collaborative effort co-financed by Innosuisse.
Natural peptide chemically optimized
The foundation of the researchers' investigation stemmed from a naturally existing peptide known as thanatin, utilized by insects as a defense mechanism against infections. A few years ago, the now retired UZH professor John Robinson discovered that thanatin disrupts a crucial lipopolysaccharide transport bridge connecting the outer and inner membranes of Gram-negative bacteria. This disruption leads to the accumulation of metabolites within the bacterial cells, ultimately resulting in their demise. However, thanatin is unsuitable for use as an antibiotic drug due to its limited effectiveness and the rapid development of bacterial resistance, among other reasons.
Consequently, the researchers proceeded to alter the chemical composition of thanatin in order to enhance its properties. "To accomplish this, structural analyses played a vital role," explains Zerbe. The team artificially constructed the distinct constituents of the bacterial transport bridge and employed nuclear magnetic resonance (NMR) techniques to observe the precise binding and disruptive mechanisms of thanatin within the transport bridge. Armed with this knowledge, researchers from Spexis AG devised the necessary chemical modifications to augment the peptide's antibacterial effects. Additional mutations were introduced to enhance the molecule's stability and address other pertinent factors.
Effective, safe and immune to resistance
Subsequently, the artificially created peptides were subjected to testing in mice afflicted with bacterial infections, yielding remarkable outcomes. "The newly developed antibiotics demonstrated exceptional efficacy, particularly in the treatment of lung infections," affirms Zerbe. "They also exhibited remarkable potency against carbapenem-resistant enterobacteria, which are impervious to the majority of other antibiotics." Furthermore, these newly devised peptides demonstrated non-toxicity and kidney safety, while also showcasing stability in the bloodstream over an extended duration – all essential characteristics for obtaining drug approval. However, additional preclinical investigations are necessary before human trials can commence.
During the peptide selection process for their study, the researchers prioritized peptides that would retain effectiveness against bacteria that had already developed resistance to thanatin. "We are confident that this approach will considerably impede the progression of antibacterial resistance," asserts Zerbe. "We now have the potential for a novel class of antibiotics to emerge, which will be effective against resistant bacteria." This development raises the prospect of combating antibiotic-resistant strains with a new arsenal of therapeutics.
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