Oral Presentation 10th Australian Peptide Conference 2013

De Novo Design Natural Xanthone Derivatives Based Peptidomimics to Mimick the Topology of Cationic Antimicrobial Peptides with Potentials for Topical Application (#47)

Shouping Liu 1 2 , Hanxun Zou 1 , Jun Jie Koh 1 , Shuimu Lin 1 , Jianguo Li 1 3 , Rajamani Lakshminarayanan 1 2 , Chandra Verma 3 , Roger Beuerman 1 2
  1. Singapore Eye Research Institute, Singapore
  2. SRP Neuroscience-Behavioral Disorders, , Duke-NUS Graduate Medical School, Singapore
  3. Bioinformatics Institute (A-STAR), Singapore

Methicillin-resistance Staphylococcus aureus (MRSA) is a predominant source of infections associated with the blood, skin and soft-tissue. In our series of studies, alpha-mangostin, a natural xanthone, which was extracted and purified from pericarp of Garcinia mangostana, has shown good activity against Gram-positive bacteria, direct interactions of α-mangostin with the bacterial membrane are responsible for the rapid concentration-dependent membrane disruption and bactericidal action; however, it has low selectivity between bacteria and mammalian cells, and less action against Gram-negative organisms [1]. A new family of xanthone derivatives was designed using alpha-mangostin-based peptidomimics to mimick the topology of cationic antimicrobial peptides. AM-0016 showed the most potent antimicrobial activity amongst the series of semi-synthetic alpha-mangostin based dicationic molecules. AM-0016 has broad spectrum antimicrobial activity with improved potency against 15 isolates of MRSA with MIC99 in the range of 0.39-1.56 μg/ml (0.59-2.35 μM), no in vivo cytotoxicity at 50 μg/ml on corneal wound healing, hemolytic activity with HC50 of 20 μg/ml tested with rabbit red blood cells, and increased selectivity index of 25-100. AM-0016 exhibited rapid in vitro bactericidal activity (3-log reduction within 10-20 minutes). In a multistep (20 passage) resistance selection study using MRSA DM21455 (source: eye), Enterococcus faecalis ATCC29212 and VISA, AM-0016 showed less than a 4-fold increase in MIC. [2] Biophysical studies together with molecular dynamics demonstrated that the amphiphilic AM-0016 was a membrane targeting antimicrobial against MRSA, disrupting bacteria membrane leading to leakage of intracellular contents within 20-30 minutes.[2] New lead compound shows excellent selectivity and in vivo activity with potential for topical application [3]. The design principle and approach provided a powerful platform for design of membrane targeting antibiotics by fine tuning the hemolytic and antimicrobial activities of xanthone based peptidomimics with potentials for topical and even systemic application to treat the infection caused by MRSA.

  1. Koh JJ, Qiu S, Zou H, Lakshminarayanan R, Li J, Zhou X, Tang C, Saraswathi P, Verma C, Tan DT, Tan AL, Liu SP, Beuerman RW., Rapid bactericidal action of alpha-mangostin against MRSA as an outcome of membrane targeting, Biochim Biophys Acta. 2013 Feb; 1828(2):834-44.
  2. Zou H, Koh JJ, Li J, Qiu S, Aung TT, Lin H, Lakshminarayanan R, Dai X, Tang C, Lim FH, Zhou L, Tan AL, Verma C, Tan DT, Chan HS, Saraswathi P, Cao D, Liu SP, Beuerman RW., Design and synthesis of amphiphilic xanthone-based, membrane-targeting antimicrobials with improved membrane selectivity, J Med Chem. 2013 Mar 28; 56(6):2359-73.
  3. Koh JJ, Lin SM, Zou H, Liu SP, Beuerman RW, et al, De novo design of xanthone derivatives based antimicrobials through mechanism of action and tuning structures, and in vivo activity evaluation , manuscript in preparation.