Public Health Research Institute Center and
Dept. Microbiology & Molecular Genetics
UMDNJ - New Jersey Medical School
225 Warren Street
Newark, New Jersey 07103

Phone: (973) 854-3364
Fax: (973) 854-3101
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. Three 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 directed 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 protect cells from lethal stresses. 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 can serve as a common, independent pathway for antimicrobial lethal action and that both the protein kinase described above and the chromosome-born toxin-antitoxin (TA) models are connected to the oxidative stress network. These findings allow integration of the TAs, the novel protein kinase, stress responses, and antimicrobial lethality into a new theme for molecular mechanism studies that will eventually lead to targets and small-molecule drugs for antimicrobial enhancement.

The third line of work explores a novel, unconventional treatment of tuberculosis. The bacterium that causes tuberculosis has infected a third of world population and kills more than 2 million people each year. Effective treatment regimens exist, but they often need to be rigidly implemented for 6 to 9 months with multiple types of chemotherapy. That often leads to serious patient non-compliance and the development of drug resistance. Indeed, the increasing prevalence of multi-drug resistance (MDR) and the emergence of extensive-drug resistance (XDR) tuberculosis may soon render all currently available treatments useless. Under a new funding initiative from the Bill and Melinda Gates Foundation, Dr. Zhao has been studying the possibility of rapid eradication of the tubercle bacillus by swiftly shifting from aerobic to anaerobic conditions. If validated, this novel, unconventional approach has the potential to cure tuberculosis (or at least to convert it from an open-lesion, contagious disease to a non-contagious carrier stage) in hours, if not minutes, rather than the months required by classical chemotherapy.




Selected Publications

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

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

Huang Q, Zheng L, Zhu Y, Zhang J, Wen H, Huang J, Niu J, Zhao X, Li Q (2011) Multicolor combinatorial probe coding for real-time PCR. PLoS One 6: e16033. PMI: 21264249

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

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

Xia X, Xu Y, Zhao X, Li Q (2009) Lateral flow immunoassay using europium chelate-loaded silica nanoparticles as labels. Clin Chem 55: 179-182. PMI: 18974359

Wang X, Zhao X (2009) Contribution of oxidative damage to antimicrobial lethality. Antimicrob Agents Chemother 53: 1395-1402. PMI: 19223646

Drlica K, Hiasa H, Kerns R, Malik M, Mustaev A, Zhao X (2009) Quinolones: action and resistance updated. Curr Top Med Chem 9: 981-998. PMI: 19747119

Zhao X, Drlica K (2008) A unified anti-mutant dosing strategy. J Antimicrob Chemother 62: 434-436. PMI: 18544596

Wu X, Wang H, Zhao X (2008) Antimicrobial studies with the Pseudomonas aeruginosa two-allele library require caution. Antimicrob Agents Chemother 52: 3826-3827. PMI: 18694947

Drlica K, Zhao X, Kreiswirth B (2008) Minimising moxifloxacin resistance with tuberculosis. Lancet Infect Dis 8: 273-275. PMI: 18471768

Drlica K, Malik M, Kerns RJ, Zhao X (2008) Quinolone-mediated bacterial death. Antimicrob Agents Chemother 52: 385-392. PMI: 17724149

Quinn B, Hussain S, Malik M, Drlica K, Zhao X (2007) Daptomycin inoculum effects and mutant prevention concentration with Staphylococcus aureus. J Antimicrob Chemother 60: 1380-1383. PMI: 17905797

Drlica K, Zhao X (2007) Mutant selection window hypothesis updated. Clin Infect Dis 44: 681-688. PMI: 17278059

Zhao X, Quinn B, Kerns R, Drlica K (2006) Bactericidal activity and target preference of a piperazinyl-cross-linked ciprofloxacin dimer with Staphylococcus aureus and Escherichia coli. J Antimicrob Chemother 58: 1283-1286. PMI: 17003060

Zhao X, Malik M, Chan N, Drlica-Wagner A, Wang JY, Li X, Drlica K (2006) Lethal action of quinolones against a temperature-sensitive dnaB replication mutant of Escherichia coli. Antimicrob Agents Chemother 50: 362-364. PMI: 16377712

Malik M, Zhao X, Drlica K (2006) Lethal fragmentation of bacterial chromosomes mediated by DNA gyrase and quinolones. Mol Microbiol 61: 810-825. PMI: 16803589

Hansen GT, Zhao X, Drlica K, Blondeau JM (2006) Mutant prevention concentration for ciprofloxacin and levofloxacin with Pseudomonas aeruginosa. Int J Antimicrob Agents 27: 120-124. PMI: 16426820

Drlica K, Zhao X, Blondeau JM, Hesje C (2006) Low correlation between MIC and mutant prevention concentration. Antimicrob Agents Chemother 50: 403-404. PMI: 16377725

Cui J, Liu Y, Wang R, Tong W, Drlica K, Zhao X (2006) The mutant selection window in rabbits infected with Staphylococcus aureus. J Infect Dis 194: 1601-1608. PMI: 17083047

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: 2008-2014. PMI: 15855526

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 acquisition of resistance. J Antimicrob Chemother 56: 1172-1175. PMI: 16207765

Shopsin B, Zhao X, Kreiswirth BN, Tillotson GS, Drlica K (2004) Are the new quinolones appropriate treatment for community-acquired methicillin-resistant Staphylococcus aureus? Int J Antimicrob Agents 24: 32-34. PMI: 15225857

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

Zinner SH, Lubenko IY, Gilbert D, Simmons K, Zhao X, Drlica K, Firsov AA (2003) Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing. J Antimicrob Chemother 52: 616-622. PMI: 12951352

Zhao X, Eisner W, Perl-Rosenthal N, Kreiswirth B, Drlica K (2003) Mutant prevention concentration of garenoxacin (BMS-284756) for ciprofloxacin-susceptible or -resistant Staphylococcus aureus. Antimicrob Agents Chemother 47: 1023-1027. PMI: 12604537

Zhao X (2003) Clarification of MPC and the mutant selection window concept. J Antimicrob Chemother 52: 731; author reply 732-733. PMI: 12972446

Lu T, Zhao X, Li X, Hansen G, Blondeau J, Drlica K (2003) Effect of chloramphenicol, erythromycin, moxifloxacin, penicillin and tetracycline concentration on the recovery of resistant mutants of Mycobacterium smegmatis and Staphylococcus aureus. J Antimicrob Chemother 52: 61-64. PMI: 12805268

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

Zhao X, Drlica K (2002) Restricting the selection of antibiotic-resistant mutant bacteria: measurement and potential use of the mutant selection window. J Infect Dis 185: 561-565. PMI: 11865411

Tillotson GS, Zhao X, Drlica K (2002) Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 347: 65-67; author reply 65-67. PMI: 12102062

Li X, Zhao X, Drlica K (2002) Selection of Streptococcus pneumoniae mutants having reduced susceptibility to moxifloxacin and levofloxacin. Antimicrob Agents Chemother 46: 522-524. PMI: 11796368

Zhao X, Drlica K (2001) Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin Infect Dis 33 Suppl 3: S147-156. PMI: 11524712

Urban C, Rahman N, Zhao X, Mariano N, Segal-Maurer S, Drlica K, Rahal JJ (2001) Fluoroquinolone-resistant Streptococcus pneumoniae associated with levofloxacin therapy. J Infect Dis 184: 794-798. PMI: 11517444

Tillotson G, Zhao X, Drlica K (2001) Fluoroquinolones as pneumococcal therapy: closing the barn door before the horse escapes. Lancet Infect Dis 1: 145-146. PMI: 11871490

Lu T, Zhao X, Li X, Drlica-Wagner A, Wang JY, Domagala J, 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: 2703-2709. PMI: 11557458

Heddle JG, Lu T, Zhao X, Drlica K, Maxwell A (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: 1219-1231. PMI: 11399091

Blondeau JM, Zhao X, Hansen G, Drlica K (2001) Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 45: 433-438. PMI: 11158737

Zhou J, Dong Y, Zhao X, Lee S, Amin A, Ramaswamy S, Domagala J, Musser JM, Drlica K (2000) Selection of antibiotic-resistant bacterial mutants: allelic diversity among fluoroquinolone-resistant mutations. J Infect Dis 182: 517-525. PMI: 10915083

Sindelar G, Zhao X, Liew A, Dong Y, Lu T, Zhou J, Domagala J, Drlica K (2000) Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria. Antimicrob Agents Chemother 44: 3337-3343. PMI: 11083637

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: 239-244. PMI: 11144424

Fournier B, Zhao X, Lu T, Drlica K, Hooper DC (2000) Selective targeting of topoisomerase IV and DNA gyrase in Staphylococcus aureus: different patterns of quinolone-induced inhibition of DNA synthesis. Antimicrob Agents Chemother 44: 2160-2165. PMI: 10898691

Dong Y, Zhao X, Kreiswirth BN, 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. PMI: 10952625

Lu T, Zhao X, Drlica K (1999) Gatifloxacin activity against quinolone-resistant gyrase: allele-specific enhancement of bacteriostatic and bactericidal activities by the C-8-methoxy group. Antimicrob Agents Chemother 43: 2969-2974. PMI: 10582891

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

Dong Y, Zhao X, Domagala J, 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. PMI: 10390236

Zhao X, Wang JY, Xu C, Dong Y, Zhou J, Domagala J, Drlica K (1998) Killing of Staphylococcus aureus by C-8-methoxy fluoroquinolones. Antimicrob Agents Chemother 42: 956-958. PMI: 9559820

Dong Y, Xu C, Zhao X, Domagala J, Drlica K (1998) Fluoroquinolone action against mycobacteria: effects of C-8 substituents on growth, survival, and resistance. Antimicrob Agents Chemother 42: 2978-2984. PMI: 9797236

Zhao X, Xu C, Domagala J, Drlica K (1997) DNA topoisomerase targets of the fluoroquinolones: a strategy for avoiding bacterial resistance. Proc Natl Acad Sci U S A 94: 13991-13996. PMI: 9391140

Drlica K, Zhao X (1997) DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol Mol Biol Rev 61: 377-392. PMI: 9293187

Liu Q, Chen X, Zhao X, Chen Y, Chen D (1992) The effect of methylation outside the recognition sequence of restriction endonuclease PvuII on its cleavage efficiency. Gene 113: 89-93. PMI: 1314209

Chen DF, Liu QA, Chen XW, Zhao XL, Chen YW (1991) The inhibition of restriction endonuclease PvuII cleavage activity by methylation outside its recognition sequence. Nucleic Acids Res 19: 5703-5705. PMI: 1945846






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)