toxins Review Macrolides: From Toxins to Therapeutics Kiersten D. Lenz , Katja E. Klosterman , Harshini Mukundan and Jessica Z. Kubicek-Sutherland * Physical Chemistry and Applied Spectroscopy, Chemistry Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA; [email protected] (K.D.L.); [email protected] (K.E.K.); [email protected] (H.M.) * Correspondence: [email protected] Abstract: Macrolides are a diverse class of hydrophobic compounds characterized by a macrocyclic lactone ring and distinguished by variable side chains/groups. Some of the most well characterized macrolides are toxins produced by marine bacteria, sea sponges, and other species. Many marine macrolide toxins act as biomimetic molecules to natural actin-binding proteins, affecting actin polymerization, while other toxins act on different cytoskeletal components. The disruption of natural cytoskeletal processes affects cell motility and cytokinesis, and can result in cellular death. While many macrolides are toxic in nature, others have been shown to display therapeutic properties. Indeed, some of the most well known antibiotic compounds, including erythromycin, are macrolides. In addition to antibiotic properties, macrolides have been shown to display antiviral, antiparasitic, antifungal, and immunosuppressive actions. Here, we review each functional class of macrolides for their common structures, mechanisms of action, pharmacology, and human cellular targets. Keywords: macrolide; toxin; antibiotic; antifungal; antiviral; antiparasitic; immunosuppressant Key Contribution: The wide range of bioactivities found in the diverse class of macrolides has promising implication for novel drug discovery. This review highlights the structure, mechanisms of action, pharmacology and human cellular interactions of a variety of macrolide compounds that may have potential therapeutic applications. Citation: Lenz, K.D.; Klosterman, K.E.; Mukundan, H.; Kubicek-Sutherland, J.Z. Macrolides: From Toxins to Therapeutics. Toxins 1. Introduction 2021, 13, 347. https://doi.org/ The study of macrolides over the past few decades has revealed a varied group 10.3390/toxins13050347 of molecules with a range of structures and functions. Macrolides are hydrophobic compounds characterized by a macrocyclic lactone ring that typically contains at least Received: 12 April 2021 12 elements, while the remaining structure varies greatly between different classes of Accepted: 8 May 2021 molecules [1,2]. Published: 12 May 2021 Many macrolides have been discovered that display pharmaceutical properties, giving them potential as antibiotic, antiviral, antiparasitic, antimycotic, or immunosuppressant Publisher’s Note: MDPI stays neutral drugs [2,3]. While naturally produced macrolides may have limited use as drugs due to with regard to jurisdictional claims in published maps and institutional affil- their instability in stomach acid, poor pharmacokinetics, and adverse side effects, synthetic iations. macrolide derivatives have been developed to overcome these issues [1]. Many macrolides also exhibit toxic bioactivity, which may be a cause of the adverse side effects observed in response to the administration of macrolide drugs. Indeed, one of the largest classes of macrolides is toxins, many of which are produced from marine sources [4]. On the other hand, some macrolide mechanisms of toxicity have been manipulated for use in Copyright: © 2021 by the authors. therapeutic applications. Licensee MDPI, Basel, Switzerland. The focus of this review was to compare and contrast five major functional classes of This article is an open access article distributed under the terms and macrolides from a variety of natural sources: toxins, antibiotics, antivirals/antiparasitics, conditions of the Creative Commons antifungals, and immunosuppressants. Each subclass has been reviewed for structural Attribution (CC BY) license (https:// similarities, mechanisms of action, pharmacology, and side effects in human beings. For creativecommons.org/licenses/by/ a comprehensive review of macrolides from marine sources, see the review written by 4.0/). Zhang et al. in 2021 [4]. Toxins 2021, 13, 347. https://doi.org/10.3390/toxins13050347 https://www.mdpi.com/journal/toxins Toxins 2021, 13, 347 2 of 27 2. Macrolide Classes 2.1. Toxins Toxins 2021, 13, x FOR PEER REVIEW Macrolide toxins originating from marine and microbial sources represent a vast3 of 37 library of chemical structures with varying mechanisms of toxicity. Marine macrolide toxins are of particular interest, as the number of known toxins has increased greatly over the past 50 years.Table Increasing1. Structure of knowledge Macrolide Toxins. of the biochemistry of these compounds has Toxins 2021, 13, x FOR PEER REVIEWexplained a wide range of toxic effects, from quick paralysis to more gradual changes3 of 37 in target cells. Marine macrolide toxins have also been of interest due to their potential Macrolide Class Compoundstherapeutic propertiesSource against * cancer and fungal or parasiticExample infections, Structure and their ability to act as immunosuppressants [3,4]. Toxins produced by bacterial species, such as the Table 1. Structure of Macrolide Toxins. mycolactones from Mycobacterium ulcerans, also have a wide range of effects on host cells, Toxins 2021, 13, x FOR PEER REVIEWmany of which have yetto be discovered [5]. 3 of 37 Kabiramide C Macrolide Class Compounds Source * Example Structure Kabiramides2.1.1. Structures Hexabranchus sp. The structuresTable 1. of Structure the macrolide of Macrolide toxins Toxins. reviewed in this paper are variable; however, Ulapualidesthe majority ofHexabranchus the structures sanguineus consist of two major components: (1) the macrocyclic ring, O O Trisoxazole- Kabiramide C which can vary in size, conjugated dienes, andO functionalN groups,O andOO (2) the acyclic side ring-containing Halichondramidechain, which is oftenChondrosia referred corticata to as the “tail”,N and can also vary in structure andN length Macrolide Class CompoundsKabiramides HexabranchusSource * sp. ExampleO Structure macrolides O between different toxins. The major subclassesN of macrolideO toxins are summarized in O Jaspisamides Jaspis sp. OH UlapualidesTable1. Hexabranchus sanguineus O O O O Trisoxazole- ONH O N 2 O OO Table 1. Structure of Macrolide Toxins. Kabiramide C ring-containing Halichondramide Chondrosia corticata N N O macrolides Kabiramides Hexabranchus sp. O Macrolide Class Compounds Source *N ExampleO Structure Mycalolides Mycale sp. O Jaspisamides Jaspis sp. OH KabiramideO C Ulapualides Hexabranchus sanguineus O O O ONH2 Trisoxazole- Kabiramides Hexabranchus sp. O N O OO Ulapualides Hexabranchus sanguineus Swinholide A ring-containing Halichondramide Chondrosia corticata N N Trisoxazole-ring- O Halichondramide Chondrosia corticata O macrolides Mycalolides Mycale sp. H containing macrolides N O Jaspisamides Jaspis sp. O Jaspisamides Jaspis sp. OH Mycalolides Mycale sp. O O H O O HO HO ONH Swinholide2 A HO Swinholides Theonella swinhoei O OH Swinholide A H O Mycalolides Mycale sp. O O Macrodiolides Ankaraholides Geitlerinema sp. O O H O O HO HO O OH O OH HO Swinholides Theonella swinhoei O OH Swinholide A O OH OH O O Swinholides Theonella swinhoei H Macrodiolides H O O Macrodiolides AnkaraholidesAnkaraholides Geitlerinema sp. O O O O H H O OH HO HO O OH HO Swinholides Theonella swinhoei O OH OH OH O O H O O O O Macrodiolides Ankaraholides Geitlerinema sp. H O ReidispongiolideO A OH O Reidispongiolide AOH OOO Reidispongiolides Reidispongia coreulea OH OH O Reidispongiolides Reidispongia coreulea H O DiterpeneDiterpene macrolactones mac- O OOO SphinxolidesSphinxolides Neosiphonia superstes ReidispongiolideH A H rolactones N O O O O OOO Reidispongiolides Reidispongia coreulea OO Diterpene mac- Sphinxolides Neosiphonia superstes O OOO H rolactones N O O O ReidispongiolideO A OO Jasplakinolides Jaspis johnstoni OOOJasplakinolide Other Reidispongiolides Reidispongia coreulea Diterpenemacrolides mac- SphinxolidesLatrunculins LatrunculiaNeosiphonia magnificasuperstes O OOO H rolactones N O O O O JasplakinolidesSpongistatin JaspisHyrtios johnstoni erecta Jasplakinolide Other OO macrolides Latrunculins Latrunculia magnifica Spongistatin Hyrtios erecta Jasplakinolides Jaspis johnstoni Jasplakinolide Other macrolides Latrunculins Latrunculia magnifica Spongistatin Hyrtios erecta Toxins 2021, 13, 347 3 of 27 Toxins 2021, 13, x FOR PEER REVIEW 4 of 37 Table 1. Cont. Macrolide Class Compounds Source * Example Structure Aplyronine Aplysia kurodai Jasplakinolide Venturicidins Streptomyces sp. Br HO NH Jasplakinolides Jaspis johnstoni MycolactoneLatrunculins MycobacteriumLatrunculia magnifica ulcerans H Spongistatin Hyrtios erecta N Other macrolides HalichondrinsAplyronine HalichondriaAplysia kurodai okadai O N Venturicidins Streptomyces sp. O Mycolactone Mycobacterium ulcerans O O Halichondrins Halichondria okadai O NH * Toxins may be produced by multiple species; one representative example is provided. 2.1.2. Mechanisms of Action * Toxins mayInhibition be produced of Actin by multiple Polymerization species; one representative example is provided. Many of the macrolide toxins discussed in this review directly interact with major components2.1.2. Mechanisms of the eukaryotic of Action cell cytoskeleton, including actin, by causing either an inhi- bition or an increase in polymerization. Cytoskeletal proteins play vital roles in eukaryotic cellInhibition health, andof Actin disruption Polymerization of the natural formation of these proteins