Bolaamphiphile Analogues of 12-bis-THA Cl <sub>2</sub> Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens
Simona Di Blasio, Maria Clarke, Charlotte K. Hind, Masanori Asai, Louis Laurence, Angelica Benvenuti, Mahnoor Hassan, Dorothy Semenya, DeDe Kwun-Wai Man, Victoria Horrocks, Giorgia Manzo, Sarah Van Der Lith, Carolyn S.P. Lam, Eugenio Gentile, Callum Annette, Janine T. Bossé, Yan-Wen Li, Barry Panaretou, Paul R. Langford, Brian D. Robertson, Jenny K.W. Lam, J. Mark Sutton, Michael McArthur, A. James Mason
Abstract
While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used.