Antibiotic resistance has been a threat to the world’s population for decades. The Lancet classifies antibiotic resistance as “one of the leading public health threats in the 21st century”. Over time, certain infectious organisms have grown resistant to various antibiotics, and new formulations are needed to combat the resistance.
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Cresomycin
Long before penicillin was used as an antibiotic agent, scientists discovered penicillinase which hydrolyzes its beta-lactam ring. Subsequently, methicillin was produced, however, we now have methicillin-resistant Staphylococcus aureus (MRSA). Mycobacterium tuberculosis is now resistant to multiple TB drugs including the potent first-line drugs, isoniazid and rifampicin.
The road to a bacteria-free world
Cresomycin, a new antibiotic successfully tested a few months ago, targets specific locations of the ribosome of various gram-positive and negative bacteria including multi-drug resistant staphylococcus aureus. Results in mice show significant inhibition of microbial activity.
The bacterial ribosome is the site of protein synthesis and mRNA translation. It consists of 30s and 50s subunits which surround the mRNA to commence translation. Antibiotics inhibit this activity by binding to locations on the subunits causing either termination of peptide bond production or translation.
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Bacteria develop resistance by synthesizing ribosomal RNA methyltransferases that cause methylation of the antibiotic rendering it ineffective.
Cresomycin is completely synthetic and its chemical structure involves a modification of the Lincosamides. It was made by a complex process called component-based synthesis.
The synthetic structure of cresomycin allows it to bypass methylation and bind to ribosomes. During the experiment, the drug showed effectiveness against E. coli, S. aureus, and P. aeruginosa both in vitro and in the test mice.
Also, they discovered features in the drug that enable it to align to bacterial ribosomal 30s and 50s subunits in succession. Moreover, the data reveal two more x-ray crystal frameworks of cresomycin bound to bacterial ribosomes that have been individually modified by the ribosomal RNA methylases, erythromycin-resistance ribosomal RNA methylase (Erm) and chloramphenicol-florfenicol resistance (Cfr).
These unique features enable the drug to adapt to whichever conformation the bacteria exhibit and it also demonstrates the meticulous modifications made by the antibiotic and target that allow cresomycin to sustain binding in situations where other antibiotics are not effective.
Clinical significance
The ability of cresomycin to bind to bacterial ribosomes without any interference is a big breakthrough in the prevention and treatment of infectious diseases. After further advancements, it can also be utilized as a prophylactic medication significantly reducing the spread and burden of infectious diseases globally.
Conclusion
Cresomycin has been tested in laboratory mice and shown to be very effective in binding to bacterial ribosomes without undergoing methylation. More studies especially in human subjects need to be done to establish more evidence and subsequently prepare the drug for release. It is believed that very soon we will be able to produce antibiotics that overcome all types of resistance.
References
Kelvin J. Y. Wu et al. ,An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance.Science383,721-726(2024). https://doi.org/10.1126/science.adk8013
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