Antimicrobial Resistance
Electron microscope image of Salmonella bacteria.
Image credit: Centers for Disease Control, 2018.
Antibiotic threats: Salmonella
Bacterial resistance to antimicrobial agents has become a major medical concern and public health emergency. According to the latest 2019 CDC report, multiple drug resistant (MDR) bacteria infect ~ 2.8 million Americans every year, and kill ~35,000 of them. Worldwide, the WHO estimates that some 700,000 people perish annually. Ominously, MDR bacteria have been increasing globally in numbers, species diversity, and number of resistance genes they carry.
So what can we do to help overcome the growing problem of antimicrobial resistance (AMR)? Widening our focus we have been learning from plants and fungi about their approach to potential bacterial invaders. Plants produce ~20-50 antibacterial compounds for their protection, which places many constraints on potentially invasive bacteria and makes it hard for them to develop resistance.
Together with Dr. Jonathan Hardy, also in the Dept. of Microbiology and Molecular Genetics, we are testing plant and fungal extracts on disease-causing bacteria that are either naturally bioluminescent or genetically engineered with a light-emitting enzyme, luciferase. Thus we can be easily monitor the survival and antibiotic resistance of the bacteria by in vivo bioluminescence imaging (BLI).
Once we understand the in vitro parameters of antibacterial activity and cytotoxicity, we will test the plant and fungal compound mixtures in mouse models of infection using these bioluminescent bacteria will allow us to test the compounds’ treatment efficacy before moving them into the clinic.
Ref.: CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA:
U.S. Department of Health and Human Services, CDC; 2019.
Our primary goal is to develop network pharmacology treatments for gastrointestinal and other infections based on plant- and fungus-based chemical compounds. Network pharmacology integrates network biology (i.e. the interactions between genome, proteome, and metabolome of cells) and polypharmacology (i.e. complex chemical compound mixtures, e.g. from plants and fungi, with therapeutic effects) to validate multiple target combinations, optimize multiple structure-activity relationships, and achieve treatment efficacy while minimizing unwanted effects.
Ref.: Andrew L Hopkins. Network pharmacology: the next paradigm in drug discovery. Nature Chemical Biology (2018) 4(11); 682- doi:10.1038/nchembio.118
In vitro testing of plant essential oils (EOs) for activity against non-typhoidal Salmonella.
Salmonella enterica serovar typhimurium SL1344 labeled with bacterial luciferase were grown to mid-log phase and then incubated with nothing (control, Row 1), mineral oil (control, Row 2), and dilutions of essential oils of clove, oregano, and thyme in mineral oil (Rows 3-8). Afterwards, light emitted by the bacteria was captured serially (from 5min to 6 hours, not shown) using a Perkin-Elmer IVIS50 system, with the last image shown here taken at 29 hours. The liquid contents of wells with 1:100 and 1:300 EO dilutions were pooled for each EO, plated overnight, and resulted in no colony growth, indicating complete killing.