Abstract
Dithiolopyrrolones are a class of antibiotics that possess the unique pyrrolinonodithiole (4H-[1,2] dithiolo [4,3-b] pyrrol-5-one) skeleton linked to two variable acyl groups. To date, there are approximately 30 naturally occurring dithiolopyrrolone compounds, including holomycin, thiolutin, and aureothricin, and more recently thiomarinols, a unique class of hybrid marine bacterial natural products containing a dithiolopyrrolone framework linked by an amide bridge with an 8-hydroxyoctanoyl chain linked to a monic acid. Generally, dithiolopyrrolone antibiotics have broad-spectrum antibacterial activity against various microorganisms, including Gram-positive and Gram-negative bacteria, and even parasites. Holomycin appeared to be active against rifamycin-resistant bacteria and also inhibit the growth of the clinical pathogen methicillin-resistant Staphylococcus aureus N315. Its mode of action is believed to inhibit RNA synthesis although the exact mechanism has yet to be established in vitro. A recent work demonstrated that the fish pathogen Yersinia ruckeri employs an RNA methyltransferase for self-resistance during the holomycin production. Moreover, some dithiolopyrrolone derivatives have demonstrated promising antitumor activities. The biosynthetic gene clusters of holomycin have recently been identified in S. clavuligerus and characterized biochemically and genetically. The biosynthetic gene cluster of thiomarinol was also identified from the marine bacterium Pseudoalteromonas sp. SANK 73390, which was uniquely encoded by two independent pathways for pseudomonic acid and pyrrothine in a novel plasmid. The aim of this review is to give an overview about the isolations, characterizations, synthesis, biosynthesis, bioactivities and mode of action of this unique family of dithiolopyrrolone natural products, focusing on the period from 1940s until now.
Highlights
There is an urgent need for new antibiotics with novel cellular targets
Dithiolopyrrolones are a group of potent antibiotic natural products that have been found in both Gram-negative and Gram-positive bacteria
The family of dithiolopyrrolonenatural products can be divided into three subfamilies: N-methyl, N-acylpyrrothine, N-acylpyrrothine and thiomarinol, a distinct group of polyketide synthase (PKS)-NRPS hybrid antibiotics
Summary
There is an urgent need for new antibiotics with novel cellular targets. Though resistance to existing antibiotics is increasing at an alarming rate, only four new structural classes of antibiotics have been introduced to the clinic in the last 50 years [1,2,3]. Dithiolopyrrolones are a group of potent antibiotic natural products that have been found in both Gram-negative and Gram-positive bacteria. 26A over 65 years ago [5], this class of molecules has intrigued numerous research groups for their unique chemical structures and their antibacterial/antifungal activities and the chemical logic and regulation of the biosynthesis. Many members of this family have already showed strong broad-spectrum activities towards Gram-positive and Gram-negative bacteria, Yeast, Fungi and even parasites [6].
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