Methillin resistant S. aureus (MRSA) was first identified in clinical specimen in 1961 - shortly after the introduction of the first beta-Iactamas resistant antibiotic - Celbenin - into clinical practice. The key component of this resistance mechanism - the mecA gene - encoding a protein with very low affinity to all beta-Iactam antibiotics - is not a native gene for S. aureus but has been acquired on multiple occasions from a ''foreign''source in the form of chromosomal cassettes. MRSA clones have emerged as major causative agents of serious and often life-threatening infections in hospitals worldwide and beginning with the late 1990s MRSA also found its way into the community. The most widely spread epidemic clones of MRSA also acquired resistance traits to the great majority of antimicrobial agents and therapeutic options against such multidrug resistant strains have become reduced to less than a handful of agents. The primary motive of this grant proposal is to find novel intervention strategies against MRSA by exploring more closely the mechanism of beta-Iactam resistance. Critical clues for such novel strategies were observations made in the two collaborating laboratories. The research program will use a combination of genetic, biochemical and metabolomic approaches and will be divided into four Specific Aims.
Aim 1 will use metabolomic approaches to identify the mechanisms by which a library of auxiliary mutants can reduce resistance level of an MRSA strain.
Aim 2 will compare the very different resistance levels produced by subpopulations of heterogeneously resistant epidemic clones of MRSA.
Aim 3 will use genome sequencing to identify determinants in the genetic background of S. aureus that control the level of resistance to oxacillin.
Aim 4 will use five contemporary isolates of MRSA recovered in Yr 2011 in New York hospital

Public Health Relevance

We are running out of antibiotics that are effective against MRSA. Based on observations made in the collaborating laboratories, this project could provide testable and novel interventions that could lower the resistance of MRSA to beta-Iactam antibiotics and other cell wall inhibitory agents.

National Institute of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Linked Specialized Center Cooperative Agreement (UL1)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-CR-3 (01))
Program Officer
Merchant, Carol
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rockefeller University
Other Domestic Higher Education
New York
United States
Zip Code
Bozzacco, Leonia; Yi, Zhigang; Andreo, Ursula et al. (2016) Chaperone-Assisted Protein Folding Is Critical for Yellow Fever Virus NS3/4A Cleavage and Replication. J Virol 90:3212-28
Gristick, Harry B; von Boehmer, Lotta; West Jr, Anthony P et al. (2016) Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site. Nat Struct Mol Biol 23:906-915
Lau, T; Bigio, B; Zelli, D et al. (2016) Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antidepressant. Mol Psychiatry :
Pereira, A C; Gray, J D; Kogan, J F et al. (2016) Age and Alzheimer's disease gene expression profiles reversed by the glutamate modulator riluzole. Mol Psychiatry :
Markowitz, Martin; Deren, Sherry; Cleland, Charles et al. (2016) Chronic Hepatitis C Virus Infection and the Proinflammatory Effects of Injection Drug Use. J Infect Dis 214:1376-1382
Karaca, N E; Aksu, G; Ulusoy, E et al. (2016) Disseminated BCG Infectious Disease and Hyperferritinemia in a Patient With a Novel NEMO Mutation. J Investig Allergol Clin Immunol 26:268-71
Ponda, Manish P; Breslow, Jan L (2016) Serum stimulation of CCR7 chemotaxis due to coagulation factor XIIa-dependent production of high-molecular-weight kininogen domain 5. Proc Natl Acad Sci U S A :
Donovan, Frank X; Kimble, Danielle C; Kim, Yonghwan et al. (2016) Paternal or Maternal Uniparental Disomy of Chromosome 16 Resulting in Homozygosity of a Mutant Allele Causes Fanconi Anemia. Hum Mutat 37:465-8
Bigio, Benedetta; Mathé, Aleksander A; Sousa, Vasco C et al. (2016) Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance. Proc Natl Acad Sci U S A 113:7906-11
Scruggs, Elizabeth; Guetterman, Timothy C; Meyer, Anna C et al. (2016) "An absolutely necessary piece": A qualitative study of legal perspectives on medical affidavits in the asylum process. J Forensic Leg Med 44:72-78

Showing the most recent 10 out of 221 publications