Cationic Bolalipid Antimicrobials
: mechanism of action and SAR

Student thesis: Doctoral ThesisDoctor of Philosophy


Antibiotic resistance is a major threat to public health as even last resort antibiotics are starting to fail and few antibiotics have been introduced over the last 20 years. This thesis focuses on the development of new antibiotics, in particular new antimicrobial bolalipids and their derivatives, based on an understanding and adaptation of the lead compound, 12-bis-THA Cl (CM2), a cationic bola-amphiphile itself adapted from the antiseptic dequalinium chloride (DQC). CM2 can encapsulate and deliver transcription factor decoy (TFD) antibiotics to bacterial cells but also has itself potent antimicrobial properties. Due to their cationic and lipophilic nature, the bolalipids were suspected of interacting strongly with bacterial plasma membranes. CM2 and DQC were confirmed to interact with models of bacterial plasma membranes, though damage (patch clamp) and lipid disordering (2H solid-state NMR) were modest and hence insufficient to explain observed differences in potency; CM2 is four times more active than DQC. DQC is known however to accumulate in bacteria and this was shown to be the case also for CM2 and hence a Structure-Activity-Relationship (SAR) study was developed to understand the main features that underpin the antimicrobial activity of this class of molecules. The SAR study comprises molecules with different bulkiness and lipophilicity. These properties were expected to affect the ability of bolalipids to cross bacterial plasma membranes and accumulate in the cytoplasm and to intercalate in nucleic acids, which would be one possible cause of bactericidal activity and host cell toxicity. The SAR study supported the importance of intracellular accumulation in bacteria in determining potency. Further, unlike in fungal pathogens, there was little or no contribution from nucleic acid binding to either bactericidal activity or host cell toxicity. Indeed, despite reducing the ability of the bolalipids to intercalate in DNA, the antibacterial activity was retained and, for some compounds, enhanced against Gram-negative bacteria. The bolalipids also act in synergy with aminoglycoside tobramycin against Pseudomonas aeruginosa with evidence produced to support a model where cationic bolalipids enhance tobramycin uptake by interfering with the bacterial respiratory chain concomitant with their accumulation within bacteria. Three different antibiotic-bola conjugates were then designed to exploit the observed accumulation and synergism. With the major finding that the most potent bolalipid analogue, Octa-bola, is both effective against Gram-negative bacteria and suited to systemic administration, this thesis offers a new perspective for the applicability of bolaamphiphiles, whose historical use was limited to that of antiseptics, as a new class of systemically administered antibiotics.
Date of Award1 Apr 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJames Mason (Supervisor) & Sukhi Bansal (Supervisor)

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