First-in-class matrix anti-assembly peptide prevents staphylococcal biofilmin vitroandin vivo

Abstract

15 Biofilm-forming bacteria are an important reservoir of nosocomial infections, and source of 16 antibiotic resistance and tolerance. These bacteria are enclosed in a complex matrix that allows 17 them to adhere to medical devices and tissue, and which also protects against antibiotics and 18 immune systems. Advances in antibiofilm strategies for targeting the biofilm matrix are therefore 19 extremely relevant in the fight against multidrug-resistant and/or -tolerant bacteria. Plants are 20 constantly attacked by a wide range of pathogens, and have protective factors such as peptides to 21 defend themselves. These peptides are common components in Capsicum red pepper seeds, and 22here we investigate and identify a new antibiofilm peptide, "capsicumicine." We demonstrate that 23 capsicumicine prevents methicillin-resistant Staphylococcus epidermidis adhesion as well as biofilm 24 establishment and maintenance via a new extracellular "matrix anti-assembly" (MAA) mechanism 25 of action. In this manner, capsicumicine disturbs the construction of the matrix, and therefore its 26 functioning. Importantly, the peptide is not an antibiotic and it is not cytotoxic, thus capsicumicine 27 is an exciting new alternative treatment for prevention of biofilm infections. 28Significance 30 Both pathogenic drug resistance and tolerance are favored by biofilm development. Indeed, biofilm-31 covered microorganisms display antibiotic resistance up to 1000 times higher than planktonic ones. 32Staphylococcus epidermidis is remarkably good at forming biofilm, and is therefore highly associated 33 with medical device infection. Here, we report the discovery of "capsicumicine," a novel antibiofilm 34 peptide derived from Capsicum bacattum. This prevents the establishment of S. epidermidis biofilm 35 via a new mechanism of action, matrix anti-assembly (MAA). MAA is not antibiotic, and is based on 36 extracellular interactions that force bacteria to remain planktonic, letting immune systems and 37 2 traditional antibiotics more easily clear the infection. For this reason, MAA should confer a lower 38 susceptibility to bacterial resistance development. Very importantly, capsicumicine is not cytotoxic. 39 Introduction 40Antimicrobial failure is a worldwide challenge, currently addressed by a WHO global action plan (1). A 41 lack of new antibiotics and the inappropriate use of older treatments mean that multidrug-resistant 42 strains are increasing (2). This process is favored by biofilm development, and microorganisms 43 enclosed in biofilm matrix have antibiotic resistance that is up to 1000 times higher than planktonic 44 ones (3-5). This makes the matrix itself an important target for biofilm control. Biofilms are organized 45 microbial clusters made of a self-assembled matrix that usually attaches to a surface, whether abiotic 46 (medical devices, teeth, etc.) or biotic (host tissues, mucus, inside chronic wounds, etc.) (6, 7). Since 47 the bacteria are embedded into this self-assembled matrix, they are harder to treat because of their 4...