Public Health Research Institute Center and
Dept. Microbiology & Molecular Genetics
New Jersey Medical School
University of Medicine and Dentistry of New Jersey
225 Warren Street
Newark, New Jersey 07103

Phone: (973) 854-3364
e-mail: zhaox5@umdnj.edu



Research Summary

Bacterial resistance, tolerance, and persistence to antimicrobial treatment pose an alarming threat to human health. Dr. Zhao’s research focuses on how to maximize our ability to combat these problems. Two lines of work are currently ongoing. First, in collaboration with Dr. Karl Drlica, he has proposed, refined, and validated the Mutant Selection Window hypothesis, which provides a new paradigm for controlling antimicrobial resistance. The hypothesis explains in part how traditional antimicrobial dosing strategies lead to resistance and suggests new ways to severely restrict the acquisition of resistance. Dr. Zhao has guided tests in animal models of infection and a small clinical trial. The selection window hypothesis is also being used to guide antibiotic dosing regimens and the development of new antimicrobial agents.


The second line of work involves understanding bacterial stress-response networks with the practical aim of developing antimicrobial potentiators. Since antimicrobial exposure constitutes one of the harshest stresses bacteria encounter, it is not surprising that genetic networks exist that can sense and respond to such stresses. By understanding and subsequently perturbing stress responses, Dr. Zhao expects to stimulate the lethal action of both antimicrobial and host immune stresses. His preliminary work has identified a previously uncharacterized gene, that when knocked out, confers hypersusceptibility to many antibacterial agents and other stresses. The product of the gene is a protein kinase that probably helps regulate stress responses. Small molecule inhibitors of the protein kinase are expected to both facilitate antimicrobial action and broaden our knowledge of bacterial stress-response networks. He has also shown that oxidative stress network can serve as a common, independent pathway for antimicrobial lethal action. Such a finding allows oxidative stress regulators and scavenging enzymes to be explored as potential targets for antimicrobial enhancement.




Recent Articles

Zhao, X., and Drlica, K. Unifying anti-mutant antimicrobial dosing strategies. (2008).
J. Antimicrob. Chemother. (in press)

Drlica, K., Zhao, X., and Kreiswirth, B. (2008).
Minimizing moxifloxacin resistance with tuberculosis.
Lancet Inf. Dis. 8: 273-275.

Drlica, K., Malik, M., Kerns, R., and Zhao, X. (2008).
Quinolone-mediated cell death.
Antimicrobial Agents Chemother. 52: 385-392

Quinn, B., Hussain, S. Malik, M., Drlica, K. and Zhao, X. (2007).
Daptomycin inoculum effects and mutant prevention concentration with Staphylococcus aureus.
J. Antimicrob. Chemother. 60: 1380-1383.

Drlica, K. and Zhao, X. (2007).
Mutant selection window hypothesis updated.
Clin. Inf. Dis 44: 681-688.

Zhao, X., Quinn, B., Kerns, R., and Drlica, K. (2006).
Bactericidal activity and target preference of a piperazinyl-crosslinked ciprofloxacin dimer with Staphylococcus aureus and Escherichia coli.
J. Antimicrob. Agents 58: 1283-1286.

Cui, J., Liu, Y., Wang, R., Tong, W., Drlica, K., and Zhao, X. (2006).
The mutant selection window in rabbits infected with Staphylococcus aureus.
J. Infect. Dis. 194: 1601-1608.

Malik M, Zhao X, Drlica K. (2006).
Lethal fragmentation of bacterial chromosomes mediated by DNA gyrase and quinolones.
Mol. Microbiol. 61: 810-825.

Hansen, G. T., Zhao, X., Drlica, K., Blondeau, J. M. (2006).
Mutant prevention concentration for ciprofloxacin and levofloxacin with Pseudomonas aeruginosa.
Int J Antimicrob Agents. 27(2):120-4.

Zhao, X., Malik, M., Chan, N., Drlica-Wagner, A., Wang, J., Li, X., Drlica, K. 2006.
Lethal action of quinolones against a temperature-sensitive dnaB replication mutant of Escherichia coli.
Antimicrobial Agents and Chemotherapy. 50: 362-364.

Drlica, K., Zhao, X., Blondeau, J., Hesje, C. (2006)
Low correlation between MIC and mutant prevention concentration.
Antimicrobial Agents and Chemotherapy 50: 403-404.

Liu, Y., Cui, J., Wang, R., Wang, X., Drlica, K., Zhao, X. (2005).
Selection of rifampicin-resistant Staphylococcus aureus during tuberculosis therapy: concurrent bacterial eradication and acquistion of resistance.
Journal of Antimicribial Chemotherapy . 56: 1172-1175.

Malik M, Lu T, Zhao X, Singh A, Hattan CM, Domagala J, Kerns R, Drlica K. (2005)
Lethality of quinolones against Mycobacterium smegmatis in the presence or absence of chloramphenicol.
Antimicrob Agents Chemother. 49(5):2008-14.

Shopsin, B., Zhao, X., Kreiswirth, B., Tillotson, G., and Drlica, K. (2004).
Are the new quinolones appropriate treatment for community-acquired methicillin-resistant Staphylococcus aureus?
Int. J. Antimicrobial Agents 24: 32-34.

Drlica K and Zhao X. (2004)
Is “dosing-to-cure” appropriate in the face of antimicrobial resistance?
Rev. Med. Microbiol. 15 (2): 73-80

Zhao X. (2003).
Clarification of MPC and the mutant selection window concept.
J. Antimicrib. Chemother. 52: 731.

Zinner S., Lubenko I., Gilbert D., Simmons K., Zhao X., Drlica K., Firsov A. (2003).
Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrationsin and out of the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing.
J. Antimicrob. Chemother. 52: 616-22.

Zhao X., Eisner W., Perl-Rosenthal N., Kreiswirth B, and Drlica K. 2003.
Potency of a new C-6 des-fluoroquinolone (BMS-284756) with Staphylococcus aureus.
Antimicrob. Agents Chemother. 47:1023-7.

Drlica K and Zhao X. (2003).
Fluoroquinolone-resistant Streptococcus pneumoniae.
Rev. Med. Microbiol. 14(3): 95-103

Lu T, Zhao X, Li X, Hansen G, Blondeau J, and Drlica K. (2003).
In vitro measurement of the mutant selection window.
J. Antimicrib. Chemother. 52: 61-64.

Zhao X and Drlica K. 2002.
Restricting the selection of antimicrobial-resistant mutant bacteria: measurement and potential use of the mutant selection window.
J. Infectious Diseases, 185: 561-5.

Li, X., Zhao, X. and Drlica, K. 2002.
Selection of Streptococcus pneumoniae mutants having reduced susceptibility to moxifloxacin and levofloxacin.
Antimicrob. Agents Chemother. 46: 522-524.

Tillotson, G., Zhao, X., and Drlica K. 2002.
Fluoroquinolone failure with pneumococci.
N Engl J Med 347(1): 65-7.

Tillotson, G., Zhao, X., and Drlica K. 2001.
Fluoroquinolones as pneumococcal therapy: closing the barn door before the horse escapes.
The Lancet Infectious Diseases 1:145-146

Urban C, Rahman N, Zhao X, Mariano N, Segal-Maurer S, Drlica K and Rahal JJ. 2001.
Fluoroquinolone-resistant Streptococcus pneumoniae associated with levofloxacin therapy.
J Infect Dis. 184(6):794-8.

Zhao, X., and Drlica, K. 2001.
Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies.
Clin Infect Dis. 33 (Suppl 3): S147-56.

Heddle, J., T. Lu, X. Zhao, K. Drlica, and A. Maxwell. 2001.
gyrB-225, a mutation of DNA gyrase that compensates for topoisomerase I deficiency: investigation of its low activity and quinolone hypersensitivity.
J Mol Biol. 309(5):1219-31.

Blondeau, J., X. Zhao and K. Drlica. 2001.
Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae.
Antimicrob. Agents Chemother. 45: 433-438.

Lu, T., Zhao, X., Li, X., Drlica-Wagner, A., Wang, J., Domagala, J., and Drlica, K. 2001.
Enhancement of Fluoroquinolone Activity by C-8 Halogen and Methoxy Moieties: Action against a Gyrase Resistance Mutant of Mycobacterium smegmatis and a Gyrase-Topoisomerase IV Double Mutant of Staphylococcus aureus.
Antimicrob Agents Chemother. 45(10):2703-9

Fournier, B., Zhao, X., Lu, T., Drlica, K., and Hooper, D. 2000.
Distribution of DNA topoisomerase IV on the bacterial chromosome: detection by selective enzyme targeting with quinolones in Staphylococcus aureus.
Antimicrob. Agents Chemother. 44: 2160-2165.

Zhou, J., Dong, Y., Zhao, X., Lee, S., Amin, A., Ramaswamy, S., J. Domagala, J. Musser, and Drlica, K. 2000.
Selection of antibiotic-resistant bacterial mutants: allelic diversity among fluoroquinolone-resistant mutants.
J. Infect. Dis. 182: 517-525.

Dong, Y., Zhao, X., Kreiswirth, B., and Drlica, K. 2000.
Mutant prevention concentration as a measure of antibiotic potency: studies with clinical isolates of Mycobacterium tuberculosis.
Antimicrob. Agents Chemother. 44: 2581-2584.

Sindelar, G., Zhao, X., Liew, A., Dong, Y., Lu, T., Zhou, J., Domagala, J., and Drlica, K. 2000.
Mutant prevention concentration (MPC) as a measure of fluoroquinolone potency against mycobacteria.
Antimicrob. Agents Chemother. 44: 3337-3343.

Shopsin B, Mathema B, Zhao X, Martinez J, Kornblum J, Kreiswirth BN. 2000.
Resistance rather than virulence selects for the clonal spread of methicillin-resistant Staphylococcus aureus: implications for MRSA transmission.
Microb Drug Resist. 6 (3):239-44

Dong, Y., Zhao, X., Domagala, J., and Drlica, K. 1999.
Effect of fluoroquinolone concentration on selection of resistant mutants of Mycobacterium bovis BCG and Staphylococcus aureus.
Antimicrob. Agents Chemother. 43: 1756-1758.

Levitz, R., Dong, Y., J.-.Y. Wang, Jeng, S.-W., Chen, C.-R., Wang, J.W., Zhao, X., Zhou., J., Lu, T., and Drlica, K. 1999.
Unintended bacteriostatic activity of hammerhead ribozymes.
Antisense and Nucleic Acids Drug Development 9: 117-123.

Drlica, K., and Zhao, X. 1999.
DNA topoisomerase IV as a quinolone target.
Current Opinion in Anti-infective Investigational Drugs 1: 435-442.

Lu, T., Zhao, X., and Drlica, K. 1999.
Gatifloxacin activity against quinolone-resistant gyrase: allele-specific enhancement of bacteriostatic and bactericidal activity by the C-8-methoxy group.
Antimicrob. Agents Chemother. 43: 2969-2974.

Zhao X, Wang J.-Y, Xu C, Dong Y, Domagala J, and Drlica K. 1998.
Killing activity of a C8-methoxy fluoroquinolone against Staphylococcus aureus.
Antimicrob. Agents. Chemother. 42: 956-958

Dong, Y., Xu, C., Zhao, X., Domagala, J., and Drlica, K. 1998.
Fluoroquinolone action against mycobacteria: effects of C8 substituents on bacterial growth, survival, and resistance.
Antimicrob. Agents Chemother. 42: 2978-2984.

Zhao X, Xu C, Domagala J, and Drlica K. 1997.
DNA topoisomerase targets of the fluoroquinolones: a strategy for avoiding bacterial resistance.
Proc. Natl. Acad. Sci. U.S.A. 94:13991-6.

Drlica, K. and Zhao, X. 1997.
DNA gyrase and topoisomerase IV as targets of the fluoroquinolones.
Microbiol and Mol Biol. Revs. 61: 377-392






C.V.

Nankai University, China, B.S. 1988
Nankai University, China, M.S. 1990
John Innes Centre, BBSRC/University of East Anglia, UK, Ph.D. 2003
Nankai University, China: 1991-1993 (Research Assistant Professor)
PHRI: 1994-present (Research Scientist, Research Associate Member)
Dept. Microbiol & Mol. Biol., UMDNJ: 2006-present (Adjunct Assistant Professor)