Supervisors: Weng Chan and Sarah Kuehne
Cutibacterium acnes (formerly Propionibacterium acnes), an aerotolerant, anaerobic Gram-positive organism, is part of the normal microbiota of the oral cavity, skin, and gastrointestinal and genitourinary tracts. The organism is a skin commensal due to its capacity to colonise the sebaceous glands and hair follicles of the human skin. However, over-colonisation by C. acnes leads to the chronic skin disease, acne vulgaris. Significantly, C. acnes can act as an opportunistic pathogen to cause invasive infections, particularly those associated with medical implants. Until recently, C. acnes has been susceptible to a wide range of antibiotics. However, over the past 2 decades, resistance to metronidazole, macrolides, clindamycin, tetracycline and trimethoprim-sulfamethoxazole has been observed with increasing frequency. Unsurprisingly, macrolide resistance is attributed to their widespread topical and oral use for clinical management of acne vulgaris.
Teixobactin, isolated from Eleftheria terrae, is a peptide antibiotic comprising of a highly constrained 13-membered tetradepsipeptide and a tethered linear heptapeptide. Mechanistically, teixobactin appeared to make strong interactions with the pyrophosphate and adjacent N-acetylmuramic acid components of lipid II. In our recent campaign to identify novel synthetic analogues of teixobactin through the installation of unnatural amino acids, we have discovered a potent analogue, VNTXB-69. When tested against Staphylococcus aureus USA300, the MIC was established to be 4 µg/mL. Significantly, VNTXB 69 is 2-fold more potent against C. acnes ATCC 11828, with MIC = 2 µg/mL.
Thus, this mini-project will entail the chemical synthesis and microbiological evaluation of novel teixobactin analogues as potential antimicrobials for the treatment of C. acnes infections especially those caused by multi-drug resistant C. acnes.
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 Ng, V, Kuehne, SA and Chan, WC (2018) Chem – Eur. J., 24, 9136.