The beauty of these Macrolones is that they kill bacteria at two different targets, interfering with both DNA topoisomerase (DNA gyrase) and ribosomes, making it difficult for bacteria to develop resistance due to random mutations in either target.
Multidrug resistance is a leading concern in public health. This phenomenon has increased both mortality and morbidity as a consequence of treatment failures. To fight multi-drug resistance, macrolides constitute an important class of drugs derived from natural product erythromycin via azithromycin and clarithromycin, especially against resistant and Gram-negative bacterial strains. Due to their low potency, research began and these new compounds called as Macrolones, a novel class of macrolides antibiotics with outstanding antibacterial potency, were introduced.
Macrolones are synthetic macrolides derivatives which possess a Quinolone moiety attached to a macrolide core. Earlier protein synthesis inhibition was thought to be the basic mechanism of these drugs but now it has been discovered that the beauty of these Macrolones is that they kill bacteria at two different targets.
The two targets are:
1). By interfering a bacterial specific enzyme (DNA topoisomerase in in vitro studies and DNA gyrase in a cell) that uncoils and folds DNA during replication,
2). They target ribosomes that act as protein synthesis inhibitors.
They either act on one target or concurrently on both site and if they hit both target at same concentration then it become difficult for bacteria to develop resistant due to random mutations in any of these targets. Macrolones are tremendously effective against well-known drug-resistant superbugs such as multidrug resistant Streptococcus pneumoniae [MDRSP], Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Staphylococcus aureus.
In conclusion, the MCX series of macrolones, which combine the scaffold of a macrolide with the side chain of a fluoroquinolone linked by a C3 bond, provide antibiotics with characteristics that outperform the drawbacks of both classes of parent medications, fluoroquinolones and macrolides. Reaching the “golden spot,” where the molecule inhibits both targets at comparatively low concentrations, requires fine-tuning the structures of the macrolide and fluoroquinolone moieties. Surprisingly, the fluoroquinolone side chains of the macrolones maintain their inhibitory effectiveness against bacterial DNA topoisomerases while providing novel ribosome contacts that enable the binding of these antibiotics to Erm-modified ribosomes and, consequently, the overcoming the resistance. Prospective avenues for enhancing this particular family of inhibitors could involve additional refinement of the fluoroquinolone moiety interactions with the ribosome. The addition of additional tiny antibiotic moieties to the macrolide scaffold may improve the macrolides’ affinity for the ribosome as well as their ability to act on non-ribosomal targets within the bacterial cell.
References:
1. Fernandes, P. Use of antibiotic core structures to generate New and useful macrolide antibiotics. In Antibiotics Current Innovations and Future Trends (eds Sánchez, S. & Demain, A. L.) (Caister Academic Press, 2015).
2. Aleksandrova, E.V., Ma, CX., Klepacki, D. et al. Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms. Nat Chem Biol (2024). https://doi.org/10.1038/s41589-024-01685-3.
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