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Towards efficacious management of microbial infections

thesis
posted on 09.12.2020, 21:04 by Caroline W Karanja

Before the 20th century infectious ailments were a central basis for morbidity and mortality globally. The introduction of effective antimicrobial agents in the mid-20th century was a turning point in medicine. Fatal diseases such as bacterial meningitis became curable, morbidity and mortality rates associated with infectious diseases reduced and surgical procedures became safer. The success of these new antimicrobial agents led many to believe problems of dealing with infectious diseases could be eradicated. This confidence soon waned due to the upsurge of drug-resistance strains. Today, rapid emergence of drug-resistance and slow introduction of new therapies are some of the contributing factors to high morbidity and mortality rates associated with infectious diseases. Consequently, to efficaciously manage drug-resistance infections, we must exercise stewardship over available resources and promote development of new antimicrobials.

To aid in antimicrobial stewardship we sought to develop a rapid azole susceptibility testing technology for Candida albicans. Candida albicans is a prevalent cause of fungal blood stream infections associated with high mortality rates. Timely administration of the appropriate antifungal is correlated positive patient’s outcome. However, timely administration is hindered by the sluggish turnovers of traditional susceptibility testing methods which take up to 72 hours. Herein, we demonstrate glucose metabolic profiling can be used as a rapid readout of fluconazole susceptibility. By probing the de novo lipogenesis, we could discriminate between a fluconazole-susceptible and fluconazole-resistant Candida albicans strain within 5 hours.

To promote development of new antimicrobial agents we conducted phenotypic screens and targeted screens in efforts to identify new chemical structures with antibacterial or antivirulence properties. From the phenotypic screen we identified alkynyl isoquinoline as Gram-positive specific antibacterial agents. In our targeted screen we identified an inhibitor of Mycobacterium tuberculosis phosphodiesterase (CdnP). CdnP facilitate immune evasion, hence we envision CdnP inhibitors could be developed into antivirulence agents. Lastly, to promote development of new antimicrobial agents we developed a facile technique for identifying inhibitors of cyclic dinucleotide (CDNs) metabolizing enzymes. Due the vital role of CDNs in bacterial physiology, CDNs metabolizing enzymes have been proposed as ideal target for development of new antimicrobial agents.


History

Degree Type

Doctor of Philosophy

Department

Chemistry

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Herman O. Sintim

Additional Committee Member 2

Hilkka I. Kenttamaa

Additional Committee Member 3

Stephen Robert Byrn

Additional Committee Member 4

Ji-Xin Cheng