Overview. Dr. Drlica’s work addresses the general problem of antibiotic resistance. Drlica and Dr. Xilin Zhao at PHRI formulated the mutant selection window hypothesis as a framework for understanding relationships between antimicrobial concentration and selective enrichment of mutant subpopulations. Expansion of these sub-populations is thought to lead to new resistance. The work reveals a flaw in the way antibiotics are currently dosed: in almost every case examined, drug concentrations inside patients fall within the selection window during much of the dosing interval. Thus, the emergence of resistance is inevitable when large numbers of prescriptions are filled. According to the window hypothesis, new compounds need to be designed so they can be dosed high enough to restrict resistant mutant enrichment.
Some antimicrobials induce bacterial resistance. To suppress this natural feature of antimicrobial treatment, it is necessary to kill pathogens quickly and reduce population size extensively (suppressing the emergence of resistance is distinct from treatment success, which often occurs with bacteriostatic agents). Thus, efforts are needed to design antimicrobial derivatives that are highly lethal, even though current versions may be lethal enough to cure most infections. Indeed, diagnostics, surveillance, drug discovery, and regulations are based largely on bacteriostatic activity (MIC) rather than on lethal action. Drlica seeks to understand antimicrobial lethality at the molecular level to design new derivatives that are more lethal. Much of the work focuses on the fluoroquinolone inhibitors of DNA gyrase as model compounds.
Fluoroquinolone resistance. The Drlica laboratory is working on two general aspects of fluoroquinolone resistance. One is to develop new derivatives that bypass existing quinolone-resistance mutations. The quinazolinediones are one example. These compounds lack a stabilizing interaction with DNA gyrase that makes them invulnerable to GyrA resistance mutations. Other stabilizing interactions have been found that improve activity. Other examples are C7 aryl fluoroquinolones. These agents appear to bind more avidly to a secondary binding mode than commercially available fluoroquinolones.
Fluoroquinolone lethality. A second line of laboratory study focuses on quinolone-mediated killing of bacteria, particularly non-growing cells of species such as Mycobacterium tuberculosis during the dormant phase of infection. The fluoroquinolones trap DNA gyrase on bacterial DNA as ternary complexes in which the DNA is broken. Rapid cell death correlates with chromosome fragmentation, which is thought to arise from release of DNA breaks from the ternary complexes. The Drlica laboratory has identified a new quinolone-binding mode in ternary complexes that may be a key to understanding why rapidly lethal concentrations are higher than those needed to block growth. Ongoing collaborations are with Xilin Zhao (PHRI), Robert Kerns (U. of Iowa), James Berger (Johns Hopkins Medical School), Hiroshi Hiasa (U. of Minnesota), and Arkady Mustaev (PHRI).
Bacterial self-destruction. Drlica is also collaborating with Xilin Zhao (PHRI) to understand bacterial self-destruction associated with lethal antimicrobials. Focus is on the connection between bacterial lesions caused by antibacterials and a cascade of reactive oxygen species thought to kill bacteria even after the initial stress is removed. One aim of this effort is to develop small-molecule enhancers of antimicrobial lethality.
Hong Y, Zeng J, Wang X, Drlica K, Zhao X (2019) Post-stress bacterial cell death mediated by reactive oxygen species. Proc Natl Acad Sci USA 116: 10064-10071. PMI: 30948634
Drlica K, Zhao X, Malik M, Hiasa H, Mustaev A, Kerns RJ (2019) Fluoroquinolone Resistance. In Bonev B and Brown N (eds.), Bacterial Resistance to Antibiotics: from Molecules to Man. Wiley Blackwell.
Copin R, Sause WE, Fulmer Y, Balasubramanian D, Dyzenhaus S, Ahmed JM, Kumar K, Lees J, Stachel A, Fisher JC, Drlica K, Phillips M, Weiser JN, Planet PJ, Uhlemann AC, Altman DR, Sebra R, van Bakel H, Lighter J, Torres VJ, Shopsin B (2019) Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus. Proc Natl Acad Sci U S A 116: 1745-1754. PMI: 30635416
Luan G, Hong Y, Drlica K, Zhao X (2018) Suppression of Reactive Oxygen Species Accumulation Accounts for Paradoxical Bacterial Survival at High Quinolone Concentration. Antimicrob Agents Chemother 62. PMI: 29229642
Luan G, Drlica K (2018) Fluoroquinolone-gyrase-DNA cleaved complexes. In Drolet M (ed.), In DNA topoisomerases: Methods in Molecular Biology. Springer Science+Business Media, New York, pp. 269-281.
Hong Y, Drlica K, Zhao X (2018) Antimicrobial-Mediated Bacterial Suicide. In Fong I, Shlaes D, and Drlica K (eds.), Antimicrobial Resistance and Implications for the 21st Century. Springer, pp. 619-642.
Drlica K, Shopsin B, Zhao X (2018) Heteroresistance: A Harbinger of Future Resistance. In Fong I, Shlaes D, and Drlica. K (eds.), Antimicrobial Resistance and Implications for the 21st Century. Springer Press, pp. 269-296.
Naqvi SAR, Drlica K (2017) Fluoroquinolones as imaging agents for bacterial infection. Dalton Trans 46: 14452-14460. PMI: 28920628
Kumar K, Chen J, Drlica K, Shopsin B (2017) Tuning of the Lethal Response to Multiple Stressors with a Single-Site Mutation during Clinical Infection by Staphylococcus aureus. Mbio 8. PMI: 29066545
Hong Y, Li L, Luan G, Drlica K, Zhao X (2017) Contribution of reactive oxygen species to thymineless death in Escherichia coli. Nat Microbiol 2: 1667-1675. PMI: 28970486