Abstract
Antibacterial discovery efforts have lagged far behind the need for new antibiotics. An approach that has gained popularity recently is targeting bacterial phospholipid membranes. We leveraged the differences between bacterial and mammalian phospholipid compositions to develop a high-throughput screen that identifies agents that selectively disrupt bacterial membranes while leaving mammalian membranes intact. This approach was used to screen 4480 compounds representing a subset of the Maybridge HitFinderTM V.11 Collection and the Prestwick Chemical Drug Library®. The screen identified 35 “positives” (0.8% hit rate) that preferentially damage bacterial model membranes. Among these, an antimalarial compound, mefloquine, and an aminoglycoside, neomycin, were identified. Further investigation of mefloquine’s activity against Staphylococcus aureus showed that it has little antibiotic activity on its own but can alter membrane fluidity, thereby potentiating a β-lactam antibiotic, oxacillin, against both methicillin-susceptible and methicillin-resistant S. aureus. This study indicates that our cell-free screening approach is a promising platform for discovering bacterial membrane disruptors as antibacterials antibiotic adjuvants.
Highlights
Antibiotic resistance is an ongoing world health concern [1]
We developed a simple and cost-effective screening approach to identify agents that selectively interact with and perturb bacterial phospholipid membranes
We selected one structural class from the hit compound set to further investigate whether the cell-free screening approach can produce hit compounds that interact with bacterial membranes of living cells
Summary
Antibiotic resistance is an ongoing world health concern [1]. In the United States alone, 2 million illnesses and 23,000 deaths are directly attributable to antibiotic resistant pathogens each year, and at the current rate, 10 million deaths annually will be directly attributable to antibiotic resistant infections [2]. In order to discover bacterial membrane perturbing agents, we set out to design a cell-free screening method using dye-loaded liposomes [15]. The extent to which the encapsulated dye de-quenches can be used as an indicator of an agent’s lytic capacity Such liposome lysis assays have been used to examine the activities of membrane targeting antibiotics and their phospholipid specificities [16,17]. We developed a cell-free high-throughput amenable method to screen and identify compounds that selectively perturb liposomes resembling bacterial membranes and leave liposomes resembling mammalian membranes intact. This effort identified mefloquine as a potential membrane-targeting antibiotic adjuvant
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