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.
Recent Book Chapters
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: (in press). PMI:
Naqvi S, Drlica K (2017) Fluoroquinolones as imaging agents for bacterial infection. . Dalton Transactions 46: 14452-14460. PMI:
Kumar K, Chen J, Drlica K, Shopsin B (2017) Dysfunction of the agr virulence regulator modulates antimicrobial-mediated killing of Staphylococcus aureus. . Mbio 8: e01476-01417. . PMI:
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:
Mi H, Wang D, Xue Y, Zhang Z, Niu J, Hong Y, Drlica K, Zhao X (2016) Dimethyl sulfoxide protects Escherichia coli from rapid antimicrobial-mediated killing. Antimicrob Agents Chemother.. Antimicrob. Agents Chemother. 60: 5954-5958. PMI:
Malik M, Mustaev A, Schwanz H, Luan G, Shah N, Oppegard L, deSouza E, Hiasa H, Zhao X, Kerns R, Drlica K (2016) Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones. Nucleic Acids Res 44: 3304-3316. PMI:
Liu Y, Zhou J, Qu Y, Yang X, Shi G, Wang X, Hong Y, Drlica K, Zhao X (2016) Resveratrol antagonizes antimicrobial lethality and stimulates recovery of bacterial mutants. . PlosOne 11: e0153023. PMI:
Zhao X, Hong Y, Drlica K (2015) Moving forward with ROS involvement in antimicrobial lethality. J Antimicrob Chemother 70: 639-642. PMI:
Long Q, Du Q, Fu T, Drlica K, Zhao X, Xie J (2015) Involvement of Holliday junction resolvase in fluoroquinolone-mediated killing of Mycobacterium smegmatis. . Antimicrob. Agents Chemother. 59: 1782-1785. PMI:
Hesje C, Drlica K, Blondeau J (2015) Mutant prevention concentration for tigecycline with clinical isolates of Streptococcus pneumoniae and Staphylococcus aureus J Antimicrob Chemother 70: 494-497. PMI:
Zhao X, Drlica K (2014) Reactive oxygen species and the bacterial response to lethal stress. . Current Opinion in Microbiology 21: 1-6. PMI:
Mustaev A, Malik M, Zhao X, Kurepina N, Luan G, Oppegard LM, Hiasa H, Marks KR, Kerns RJ, Berger JM, Drlica K (2014) Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding. J. Biol. Chem 289: 12300-12312. PMI:
Malik M, Li L, Zhao X, Kerns RJ, Berger JM, Drlica K (2014) Lethal synergy involving bicyclomycin: an approach for reviving old antibiotics. . J. Antimicrob Chemother. 89 3227-3235. PMI:
Li L, Hong Y, Luan G, Mosel M, Malik M, Drlica K, Zhao X (2014) Ribosomal elongation factor-4 promotes cell death associated with lethal stress. Mbio 5: e01708 PMI:
Drlica K, Mustaev A, Towle T, Luan G, Kerns R, Berger J (2014) Bypassing fluoroquinolone resistance with quinazolinediones: studies of drug-gyrase-DNA complexes having implications for drug design. . ACS Chemical Biology 9: 2895-2904. PMI:
Mosel M, Li L, Drlica K, Zhao X (2013) Superoxide-mediated protection of Escherichia coli from antimicrobials. Antimicrob Agents Chemother 57: 5755-5759. PMI: 23979754
Metzler K, Drlica K, Blondeau JM (2013) Minimal inhibitory and mutant prevention concentrations of azithromycin, clarithromycin and erythromycin for clinical isolates of Streptococcus pneumoniae. J Antimicrob Chemother 68: 631-635. PMI: 23169894
Dorsey-Oresto A, Lu T, Mosel M, Wang X, Salz T, Drlica K, Zhao X (2013) YihE kinase is a central regulator of programmed cell death in bacteria. Cell Rep 3: 528-537. PMI: 23416055
Malik M, Chavda K, Zhao X, Shah N, Hussain S, Kurepina N, Kreiswirth BN, Kerns RJ, Drlica K (2012) Induction of mycobacterial resistance to quinolone class antimicrobials. Antimicrob Agents Chemother 56: 3879-3887. PMI: 22564842
Wu X, Wang X, Drlica K, Zhao X (2011) A toxin-antitoxin module in Bacillus subtilis can both mitigate and amplify effects of lethal stress. PLoS One 6: e23909. PMI: 21897862
Marks KR, Malik M, Mustaev A, Hiasa H, Drlica K, Kerns RJ (2011) Synthesis and evaluation of 1-cyclopropyl-2-thioalkyl-8-methoxy fluoroquinolones. Bioorg Med Chem Lett 21: 4585-4588. PMI: 21705218
Malik M, Marks KR, Mustaev A, Zhao X, Chavda K, Kerns RJ, Drlica K (2011) Fluoroquinolone and quinazolinedione activities against wild-type and gyrase mutant strains of Mycobacterium smegmatis. Antimicrob Agents Chemother 55: 2335-2343. PMI: 21383100
Liang B, Bai N, Cai Y, Wang R, Drlica K, Zhao X (2011) Mutant prevention concentration-based pharmacokinetic/pharmacodynamic indices as dosing targets for suppressing the enrichment of levofloxacin-resistant subpopulations of Staphylococcus aureus. Antimicrob Agents Chemother 55: 2409-2412. PMI: 21343454
Wang X, Zhao X, Malik M, Drlica K (2010) Contribution of reactive oxygen species to pathways of quinolone-mediated bacterial cell death. J Antimicrob Chemother 65: 520-524. PMI: 20067982
Oppegard LM, Streck KR, Rosen JD, Schwanz HA, Drlica K, Kerns RJ, Hiasa H (2010) Comparison of in vitro activities of fluoroquinolone-like 2,4- and 1,3-diones. Antimicrob Agents Chemother 54: 3011-3014. PMI: 20404126
Malik M, Marks KR, Schwanz HA, German N, Drlica K, Kerns RJ (2010) Effect of N-1/c-8 ring fusion and C-7 ring structure on fluoroquinolone lethality. Antimicrob Agents Chemother 54: 5214-5221. PMI: 20855738
Malik M, Hoatam G, Chavda K, Kerns RJ, Drlica K (2010) Novel approach for comparing the abilities of quinolones to restrict the emergence of resistant mutants during quinolone exposure. Antimicrob Agents Chemother 54: 149-156. PMI: 19805561
Han X, Dorsey-Oresto A, Malik M, Wang JY, Drlica K, Zhao X, Lu T (2010) Escherichia coli genes that reduce the lethal effects of stress. BMC Microbiol 10: 35. PMI: 20128927
Fong, I.W., Shlaes, D. and Drlica, K. eds. (in press).
Antimicrobial Resistance and Implications for the 21st Century.
(Springer Press, Second Edition)
Drlica, K., and Perlin, D.S. (2011).
(FT Press: Science)
Fong, I.W., and Drlica, K. eds. (2008).
Antimicrobial Resistance and Implications for the 21st Century.
Drlica, K. (2003).
Understanding DNA: A Guide for the Curious.
(John Wiley & Sons, Fourth Edition)