Dual Agents: Fungal Macrocidins and Synthetic Analogues with Herbicidal and Antibiofilm Activities

• Main Authors: Laura Treiber, Christine Pezolt, Haoxuan Zeng, Hedda Schrey, Stefan Jungwirth, Aditya Shekhar, Marc Stadler, Ursula Bilitewski, Maike Erb-Brinkmann, Rainer Schobert
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Antibiotics
• Subjects: macrocidin; polycyclic tetramate macrolactams; 3-acyltetramic acids; antibiotics; biofilms
• Online Access: https://www.mdpi.com/2079-6382/10/8/1022

Eight analogues of the bioherbicides macrocidin A (<b>1</b>) and Z (<b>2</b>) with structural variance in the size of the macrocycle, its <i>para</i>- or <i>meta</i>-cyclophane character, and its functional groups were synthesized on two modular routes and tested for herbicidal, antibiotic, and antibiofilm activities. Apart from the lead compounds <b>1</b> and <b>2</b>, the structurally simplified dihydromacrocidin Z (<b>3</b>) and normacrocidin Z (<b>4</b>) showed high herbicidal activity in either thistles, dandelions or in both. The derivatives <b>2</b>, <b>3</b>, and dibromide <b>9</b> also inhibited the growth of <i>Staphylococcus aureus</i> biofilms by ca 70% when applied at subtoxic concentrations as low as ca 20 µM, which are unlikely to induce bacterial resistance. They also led to the dispersion of preformed biofilms of <i>S. aureus</i>, exceeding a similar effect by microporenic acid A, a known biofilm inhibitor. Compounds <b>3</b> and <b>9</b> showed no noticeable cytotoxicity against human cancer and endothelial cells at concentrations below 50 µM, making them conceivable candidates for application as anti-biofilm agents in a medicinal context.