- Post Doctoral
MIT Unit Affiliation:
- Biological Engineering
- Electrical Engineering & Computer Science
Post Doc Sponsor / Advisor:
Date PhD Completed:
Top 3 Areas of Expertise:
Dr. Cesar de la Fuente is a Postdoctoral Associate and Areces Foundation Fellow with Prof. Timothy K. Lu at the Massachusetts Institute of Technology (MIT). His research focuses on discovering novel therapeutics to treat infectious diseases using a convergence science approach. At MIT, Dr. de la Fuente is expanding his expertise in peptide engineering, synthetic and computational biology. He previously completed postdoctoral research at the University of British Columbia, where he also received his Ph.D. in Microbiology and Immunology in 2014 as a La Caixa Foundation Fellow. He has published >40 papers and is inventor and co-inventor of multiple patents. He has received numerous awards, including most recently being recognized by MIT Technology Review as an “Innovator Under 35” and being named “30 Under 30 Latino Boston”.
Expected End Date of Post Doctoral Position:
- Peptide nanomedicines and nanomaterials- Synthetic and Computational Peptide Drug Design
- Peptide Design for Antimicrobial Applications
- Genetic Algorithms for Artificial Directed Evolution of Peptides
- Synthetic Biology of Peptide Molecules
- Microbiome Engineering
Bacteria form multicellular communities known as biofilms that cause two
thirds of all infections and demonstrate increased adaptive resistance to conventional
antibiotics. Currently, there are no approved drugs that specifically target bacterial
biofilms. In this work, I first identified peptide 1037, which inhibited biofilm formation in
a broad-spectrum manner and proposed that this activity might be due to the effect of
the peptide on biofilm-associated processes. However, these processes are not
widespread in bacteria and therefore did not explain the broad-spectrum activity of
the peptide. Additional screens identified 1018 as a potent anti-biofilm peptide that
prevented biofilm formation and led to the eradication of mature biofilms in both
Gram-negative and Gram-positive bacteria. Low levels of the peptide led to biofilm
dispersal, while higher doses triggered biofilm cell death. To explain the broadspectrum
activity of the peptide, I hypothesized that it acted to inhibit a common
stress response, and that the stringent response, mediating (p)ppGpp synthesis
through the enzymes RelA and SpoT, was targeted. Consistent with this notion,
increasing (p)ppGpp synthesis led to reduced susceptibility to the peptide.
Furthermore, relA and spoT mutations blocking production of (p)ppGpp replicated the
effects of the peptide, leading to reduced biofilm formation. Eliminating (p)ppGpp
expression after 2 days of biofilm growth by removal of arabinose from a strain
expressing relA behind an arabinose-inducible promoter, reciprocated the effect of
peptide added at the same time, leading to loss of biofilm. NMR and chromatography
studies showed that the peptide acted on cells to cause degradation of (p)ppGpp, and
in vitro directly interacted with ppGpp. These results indicate that 1018 targets
(p)ppGpp and marks it for degradation, thus providing an explanation for the broadspectrum
activity of the peptide. Further, the peptide was found to be synergistic with
different classes of antibiotics to prevent and eradicate bacterial biofilms. Thus the
peptide represents a novel strategy to potentiate antibiotic activity against biofilms.
Further studies identified even more potent D-enantiomeric anti-biofilm peptides DJK-
5 and DJK-6 that also prevented (p)ppGpp accumulation, were highly synergistic with
conventional antibiotics and exhibited in vivo activity. Targeting biofilms represents a
novel approach against drug-resistant bacterial infections.
Top 5 Awards and honors (name of award, date received):
5 Recent Papers:
O.N. Silva *, C. de la Fuente-Núñez* et al. “An anti-infective synthetic peptide with dual antimicrobial and
immunomodulatory activities”, Scientific Reports, 2016, In press. Co-corresponding author.
C. de la Fuente-Núñez, and T.K. Lu, “CRISPR-Cas technology for microbial synthetic biology: applications in genome engineering and development of sequence-specific antimicrobials”, Integrative Biology, 2017, In press. Co-corresponding author.
A.D. Verderosa*, C. de la Fuente-Núñez* et al., “Ciprofloxacin-nitroxide hybrids with potential for biofilm eradication”, Eur J Med Chem, 2017, In press.
C. de la Fuente-Núñez, Torres M, Mojica F, and T.K. Lu, “Next-generation precision antimicrobials: towards personalized treatment of infectious diseases”, Current Opinion Microbiology, 2017, 14;37:95-102. Co-corresponding author.