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Scientific Overview Research Interest Summary Principal Investigators    Yuri Bushkin, Ph.D.
   Theresa Chang, Ph.D.
   Neeraj Chauhan, Ph.D.
   Véronique Dartois, Ph.D.
   Thomas Dick, Ph.D.
   Karl Drlica, Ph.D.
   David Dubnau, Ph.D.
   Eliseo A. Eugenin, Ph.D.
   Marila Gennaro, M.D.
   Fred Kramer, Ph.D.
   Barry Kreiswirth, Ph.D.
   Min Lu, Ph.D.
   Leonard Mindich, Ph.D.
   Arkady Mustaev, Ph.D.
   Jyothi Nagajyothi, Ph.D.
   David Perlin, Ph.D.
   Abraham Pinter, Ph.D.
   Marcela Rodriguez, Ph.D.
   Jeanne Salje, Ph.D.
   Lanbo Shi, Ph.D.
   Selvakumar Subbian, Ph.D.
   Sanjay Tyagi, Ph.D.
   Christopher Vinnard, M.D.
   Chaoyang Xue, Ph.D.
   Xilin Zhao, Ph.D.

   Research Faculty
   Liang Chen, Ph.D.
   Eugenie Dubnau, Ph.D.
   Jeanette Hahn, Ph.D.
   Salvatore Marras, Ph.D.
   Yanan Zhao, Ph.D.

Emeritus Faculty Recent Publications
 
Karl Drlica, Ph.D.

Research Summary  |  Selected Publications  |  Book Chapters
Symposium Chapters  |  Books Authored  |  Books Edited
Other Sponsored Work

 

Public Health Research Institute Center
New Jersey Medical School - Rutgers, The State University of New Jersey
225 Warren Street
Newark, New Jersey 07103

Phone: (917) 821-6847
e-mail: drlicaka@njms.rutgers.edu



Research Summary

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 also seeks to understand how some antimicrobials rapidly kill bacteria to facilitate the design of compounds that quickly lower pathogen burden during infection. This type of work is expected to be important, because current antimicrobial use is based on a bacteriostatic measurement (MIC) rather than on killing. Lethal action is expected to be significant when antimicrobial consumption is high and immune-suppression is widespread, as is currently the case.

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. Another example are C7 aryl fluoroquinolones. These agents appear to bind more avidly to a secondary binding mode than commercially available fluoroquinolones.

The second aspect of resistance concerns identifying antibiotic doses that restrict the emergence of resistance. Early work showed that resistant bacterial mutants are selectively enriched when drug concentrations fall inside a range called the mutant selection window. The selection window idea has now been tested with fluctuating drug concentrations in vitro and in an animal model with Staphylococcus aureus. The hypothesis has also passed a small clinical test in which S. aureus resistance developed at the same time susceptible populations were eradicated. Moreover, the hypothesis explains why clinical resistance is higher with some macrolides than with others.

The selection window hypothesis reveals a fundamental flaw in our current antimicrobial dosing strategies: almost all antimicrobial treatment protocols place drug concentrations inside the selection window for long periods of time. Restricting the emergence of resistance requires increasing doses in addition to the accepted practice of reducing unnecessary use. Persons interested in early selection window publications are referred to MSW papers 

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. 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 antimicrobials.

Honors and Awards

NIH Research Career Development Award
Holmes Memorial Lecture (Florida Institute of Technology)
Heikkila Memorial Lecture (University of Medicine and Dentistry of New Jersey)
Alumni Fellow (Oregon State University)
Christopher Mathews Lecture (Oregon State University)
Professional Night Speaker (College Board Reviewers)
Mentor of the Year (New Jersey Medical School, UMDNJ)




Selected Publications

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




Book Chapters

Drlica, K, Zhao, X, Malik, M, Salz, Tal, and Kerns R (2012). Fluoroquinolone Resistance: Mechanisms, Restrictive Dosing, and Anti-mutant Screening Strategies for New Compouds. In Antibiotic Discovery and Development, T Dougherty and M Pucci Ed., Springer New York, Dordrecht, Heidelberg, London.

Drlica, K., and Bendich, A. (2009) Chromosome, Bacterial In Encyclopedia of Microbiology, M. Schaechter, Ed. p. 507-516.

Drlica, K., Zhao, X., and Malik, M. (2009) Pathogenesis: Quinolones In Encyclopedia of Microbiology, M. Schaechter, Ed. p. 707-716.

Drlica, K., Wang, J.-Y., Malik, M., Lu, T., Logan, C., Park, S., Li, X., Perlin, D., Zhao, X. (2008). An anti-mutant approach for antimicrobial use. In Antimicrobial Resistance and Implications for the 21st Century, I. Fong, K. Drlica, eds. Springer: New York. p. 371-400.

Wang. J.-Y. and Drlica, K. (2007) Selection of Target Sites in RNA for Antisense Agents. In Antisense Elements (Genetics) Research Focus, Ed.: A.G. Hernandez. Nova Science Publishers, Inc. p. 71-89.

Drlica, K., Lu, T., Malik, M., and Zhao, X. (2004). Fluoroquinolones as antituberculosis agents. In Tuberculosis, W. Rom and S. Garay, eds. pp. 791-807.

Drlica, K. and Hooper, D. (2003). Mechanism of quinolone action. In The Quinolones, D. Hooper, ed. American Soc. Microbiology: Washington, pp.19-40.

Drlica, K. and Zhao, X. (2003). Controlling antibiotic resistance: strategies based on the mutant selection window. In Re-emergence of established microbial pathogens in the 21st century, I.W. Fong and K. Drlica, eds., Kluwer Academic Plenum Publishers, pp. 295-331.

Drlica, K. and Gennaro, M. (2001). Plasmids. In Encyclopedia of Genetics, S. Brenner and J. Miller, editors-in-chief, Academic Press pp. 1485-1490.

Drlica, K. and Bendich, A. (2000). Chromosome, Bacterial. In Encyclopedia of Microbiology, J. Lederberg, ed. second edition; p. 808-821.

Drlica, K., Wu, E.-D., C.-R. Chen, J.-Y. Wang, Zhao, X., Xu, C., Qiu, L., Malik, M., Kayman, S., and Friedman, M. (1999). Prokaryotic DNA topology. In Prokaryotic Gene Expression (Frontiers in Molecular Biology); edited by S. Baumberg, ed. pp. 141-168.

Drlica, K. and Woldringh, C. (1998).
Chromosomal organization: nucleoids, chromosomal folding, and DNA topology. In Bacterial Genomes: Physical Structure and Analysis, edited by F. de Bruijn, J. Lupski, and G. Weinstock. pp 12-22.
Drlica, K., Malik, M., Wang, J.-Y, Levitz, R., and R. Burger. (1996). The fluoroquinolones as antituberculosis agents. In Tuberculosis, edited by W. Rom and S. Garay; Little, Brown and Co, NY. 817-827.

Drlica, K. (1992). The bacterial chromosome. In Encyclopedia of Microbiology, edited by J. Lederberg 1: 517-527.

Drlica, K and Riley, M. (1990).
An historical introduction to the bacterial chromosome. In The Bacterial Chromosome, K. Drlica and M. Riley, eds, American Society for Microbiology: Washington, D.C. pp. 3-13.

Drlica, K., Pruss, G., Burger, R. Franco, R., Hsieh, L., and Berger, B. (1990). Roles of DNA topoisomerases in bacterial chromosome structure and function. In The Bacterial Chromosome, K. Drlica and M. Riley, eds, American Society for Microbiology: Washington, D.C. pp. 195-204.

Drlica, K., Coughlin, S., and Gennaro, M. (1990). Mode of action of quinolones: biochemical aspects. In The New Generation of Quinolones, J. Domagala, C. Heifetz, and C. Siporin, eds., Marcel Dekker Press pp. 45-62.

Drlica, K. (1990). Genetic Engineering: The Gene. In Comprehensive Medicinal Chemistry, Volume 1; P.D. Kennewell, editor. Pergamon Press. p. 361-408.

Drlica, K. (1987). The Nucleoid. In Escherichia coli and Salmonella typhimurium: Cellular and Molecular Biology, F. Neidhardt, ed. 91-103.




Symposium Chapters

Drlica, K., and Zhao., X. (2008). Mutant selection window hypothesis: a framework for anti-mutant dosing of antimicrobial agents. In National Institute of Allergy and Infectious Diseases, NIH Volume 1, Frontiers in Research, V. Georgiev, Editor. Humana Press Inc., Totawa, NJ. pp 101-106.

Drlica, K. (1999). Mechanisms of fluoroquinolone action and resistance. In First International Moxifloxacin Symposium, Berlin, 1999; L. Mandell, Ed. pp 75-83.

Burger, R., and Drlica, K. (1996). Bleomycin reaction pathways: kinetic approaches. In DNA Cleavers and Chemotherapy of Cancer or Viral Diseases, edited by B. Meunier, Kluwer Academic Publishers, Dordrecht, pp 91-106.

Rouviere-Yaniv, J., Kiseleva, E., Almeida, A., and Drlica, K. (1992). Protein HU and DNA supercoiling. In Prokaryotic Structure and Function: A New Perspective, edited by. S. Mohan, C. Dow, and J. Cole. Soc. for General Microbiol. Symp. 47:414-438.

Hsieh, L.-S., Burger, R.M., and Drlica, K. (1990). DNA topoisomerases and the bacterial chromosome. In Structural and Organizational Aspects of Metabolic Regulation, UCLA Symposia on Molecular and Cellular Biology, New Series, Volume 134, P. Srere, M.E. Jones, and C. Mathews, eds., Alan R. Liss, Inc., New York, NY pp. 153-164.

Franco, R., T. Steck, S. Chevalier, and K. Drlica. (1987). Bacterial topoisomerase mutations: effects on abundance of proteins and suppression of gyrB by rpoB. In Mechanisms of DNA Replication and Recombination, UCLA Symposia on Molecular and Cellular Biology, New Series. 47: 533-541.

Drlica, K., G. J. Pruss, S. H. Manes, and S. G. Chevalier. (1986). DNA topoisomerase mutations in bacteria. In Bacterial Chromatin, C. Gualerzi, ed. Springer-Verlag. pp. 52-63.

Drlica, K. and A. Worcel. (1975). Viscometric analysis of conformational transitions in the Escherichia coli chromosome. DNA Replication: ICN-UCLA Symposium on Molecular Biology (F. Fox and P. Hanawalt, eds.). pp 138-158.




Books Authored

Drlica, K., and Perlin, D.S. (2011). Antibiotic Resistance. (FT Press: Science)

Drlica, K. (2003). Understanding DNA: A Guide for the Curious. (John Wiley & Sons, Fourth Edition)

Drlica, K. (1997). Understanding DNA: A Guide for the Curious. (John Wiley & Sons, Third Edition).

Drlica, K. (1996). Double-Edged Sword: The Promises and Risks of the Genetic Revolution. Addison-Wesley 242 pp. (revised paperback edition).

Drlica, K. (1994). Double-Edged Sword: The Promises and Risks of the Genetic Revolution. Addison-Wesley 242 pp.

Drlica, K. (1992). Understanding DNA and Gene Cloning: A Guide for the Curious. John Wiley & Sons, 2nd edition 240 pp. (edtions in English and German).

Drlica, K. (1984). Understanding DNA and Gene Cloning: A Guide for the Curious. John Wiley and Sons, Inc. 205 pp. (editions in English, Japanese, and Italian).




Books Edited

Fong, I.W. and Drlica, K. eds. (2008). Antimicrobial Resistance and Implications for the 21st Century Springer Science+Business Media, pp 407.

Fong, I.W., and Drlica, K. eds. (2003). Re-emergence of established microbial pathogens in the 21st century. Kluwer/Plenum Press, pp. 367.

Drlica, K. and Riley, M., eds. (1990). The Bacterial Chromosome. American Society of Microbiology: Washington 469 pp.




Other Sponsored Work

Wang, X. and Zhao, X. (2009). Contribution of oxidative damage to antibiotic lethality. Antimicrob. Agents Chemother. 53:1395-1402.

Wu, X., Wang, H., and Zhao, X. (2008). Antimicrobial studies with the Pseudomonas aeruginosa two-allele library require caution. Antimicrob. Agents Chemonther. 52: 3826-3827.

Zhao X. (2003). Clarification of MPC and the mutant selection window concept. J Antimicrob Chemother. 2003 Oct;52(4):731; author reply 732-3. Epub 2003 Sep 12. PMID: 12972446

Lu, T., Malik, M., and Drlica-Wagner, A. (2001). C-8-methoxy fluoroquinolones. Research Advances in Antimicrobial Agents & Chemother. 2001;2:29-42.

Wang, J.-Y. (1998). Mathematical relationships among DNA supercoiling, cation concentration, and temperature for prokaryotic transcription. Mathematical Biosciences. 1998;151:155-63.

Pruss, G. (1985). DNA topoisomerase I mutants: increased heterogeneity in linking number and other replicon-dependent changes in DNA supercoiling. J. Mol. Biol. 1985;185:51-63.

 
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