Review article14- and 15-membered lactone macrolides and their analogues and hybrids: structure, molecular mechanism of action and biological activity
Graphical abstract
Introduction
The term “macrolide,” proposed for the first time by Woodward in 1957, is used to describe natural antibiotics consisting of 12-16–membered macrocyclic lactone ring, functionalised by double bonds, and bearing different saccharide and aminosaccharide components [1]. Among lactone macrolides, those possessing 14-, 15-, and 16-membered aglycone rings (Fig. 1) constitute an important family of natural origin. Members of this family show a wide range of biological potency and possess antibacterial (especially against Gram-positive and some Gram-negative organisms such as Bordetella pertussis and Legionella pneumophila), anti-inflammatory, antimalarial, and anticancer activity [[2], [3], [4], [5], [6], [7], [8], [9], [10], [11]]. Macrolides can have undesirable side effects such as hepatotoxicity, allergic reactions, or disturbances of the gastrointestinal tract [[12], [13], [14]]. Classical antibacterial lactone macrolides (1–4, Fig. 1) bind near the PTC-loop with the 50S subunit of bacterial ribosomal tunnel filled with water. This occurs because classical antibacterial lactone macrolides have 14–16 membered aglycone ring revealing hydrophobic and hydrophilic sides and relatively polar saccharide units [[15], [16], [17], [18]]. The amino-saccharide parts of aglycone rings in 14- and 15-membered macrolide antibiotics play an important role in interactions with cell membranes, and are essential for transporting the drug to its target site [19]. Natural 16-membered macrolactones include compounds with atypical biological activity; these include avermectin B1a (compound 5), which was isolated from a soil sample at the Kitasato Institute. Unlike typical lactone macrolide antibiotics, avermectin B1a possesses antiparasitic and insecticide activity, but is not an effective antibacterial agent [20]. Macrolactones show vast structural diversity due to the presence of smaller and larger lactone rings (Fig. 1). Natural lactone antibiotics include those produced by Streptomyces strains, such as 26-membered oligomycin A (6, inhibitor of ATP-synthase), which possesses a spiro-ketal moiety instead of saccharides [21,22]; and 36-membered strong antifungal agents such as amphotericin B (7) and nystatin A1 (8), which are structurally closer to polyene antibiotics due to the presence of polyunsaturated aglycones [23,24]. Examples of natural lactones, not bearing saccharides and isolated from yeasts, include isomeric 12-membered cruentaren A (cmpd. 9, having anticancer activity) and 6-membered cruentaren B (cmpd. 10, biologically inactive) [25]. However, the latter is not classified as a macrolide due to its small ring.
Section snippets
Structure of 14- and 15-membered lactone antibiotics and their molecular mechanism of biological action vs. that of 16-membered macrolides
14-membered lactone antibiotics as e.g. erythromycin A (1, Fig. 1) and clarithromycin (2, Fig. 1) are present in two families of conformations, the so-called folded-in and folded-out ones, as postulated by Everett and Tyler as well as Barber et al. [[26], [27], [28]]. Studies using NMR have shown that in solution, 1 (gray, Fig. 2) exists mainly in the typical lowest-energy folded-out conformation, where proton H8 has no 1H–1H contact with H4 and H11 (Fig. 2) [28,29]. Instead of it, the
Bacteria resistance and chemical instability decreasing antibacterial potency of 14- and 15-membered ring lactone macrolide antibiotics
The presence of antibiotics and their metabolites in the environment constitutes a serious global problem that affects human life and safety. Because lactone macrolides are widely used in medical treatment, bacteria are rapidly developing resistance to these antibiotics, as illustrated by the presence of antibiotic-resistant bacteria and genes (ARGs) in wastewater [[55], [56], [57]]. Bacterial resistance to the typical 14-, 15-, and 16-membered lactone antibiotics is often realised by covalent
Modifications of 14-membered macrolides within cladinose
Binding assessments of simple 14- and 15-membered macrolides show that cladinose is necessary for achieving high antibacterial potency, as shown by 1st and 2nd generation (1–3) macrolides [11]. Ketolides are third generation macrolide antibiotics that include telithromycin (11), cethromycin (18), solithromycin (19),
TE-802 (20a), and modithromycin (20b) (Fig. 5, Fig. 8). Despite ketolides do not contain a cladinose they show a high antibacterial potency because their arms are extended via
Conclusions and outlook
Although numerous studies have examined the medicinal chemistry of 14- and 15-membered lactone macrolides, the therapeutic potency of this group of antibiotics remains not fully revealed. In addition to superior antibacterial and bactericidal properties, these macrolides also show promising anti-inflammatory, antimalarial, anticancer, and antileishmanial activity, and may be useful in regulation of gastrointestinal motility. Hence, 14- and 15-membered classical macrolides, as well as their
Acknowledgements
The authors are grateful for the financial support from the Polish National Science Centre (NCN) - OPUS 10 project no. UMO-2015/19/B/ST5/00231.
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