- Post Doctoral
MIT Unit Affiliation:
- Biological Engineering
- Electrical Engineering & Computer Science
Post Doc Sponsor / Advisor:
Date PhD Completed:
Top 3 Areas of Expertise:
César de la Fuente, Ph.D. is a Postdoctoral Associate at MIT and the Broad Institute of MIT and Harvard University. César obtained his Ph.D. in Microbiology and Immunology at the University of British Columbia, and received his B.Sc., M.Sc. in Biotechnology at University of Leon.
His research interests include small cationic peptides as novel anti-biofilm agents and modulators of innate immunity, and the development of these drugs to combat antibiotic-resistant infections that are currently untreatable.
César believes the answer to the global health problem of antibiotic resistance can be found in nature, and has pioneered the discovery of several classes of next-generation, bioinspired antimicrobials derived from naturally-occurring molecules such as cationic host defense peptides and nitric oxide.
César has published over 20 papers and reviews, and presented at more than 15 conferences. He is co-inventor of a provisional patent application on the use of cationic anti-biofilm and innate defense regulator (IDR) peptides (U.S. Patent Application No. 61/870,655). César is a recipient of several awards, including a prestigious Doctoral Scholarship from “la Caixa” Foundation awarded by the King and Queen of Spain, a Barrie Foundation Young Investigator Award, and a Postdoctoral Fellowship from Ramón Areces Foundation.
Expected End Date of Post Doctoral Position:
- Next-generation bioinspired antibiotics to combat antibiotic resistance
- CRISPR-Cas-based intelligent antimicrobials
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:
de la Fuente-Núñez C et al., "D-enantiomeric peptides that eradicate wild-type and multi-drug resistant biofilms and protect against lethal Pseudomonas aeruginosa infections". Chemistry & Biology. 2015; 22:196–205.
de la Fuente-Núñez C et al., "Anti-biofilm and immunomodulatory activities of peptides that inhibit biofilms formed by pathogens isolated from cystic fibrosis patients". Antibiotics. 2014; 3:509-526.
Reffuveille F, de la Fuente-Núñez C, Mansour S, Hancock REW. "A broad-spectrum anti-biofilm peptide enhances antibiotic action against bacterial biofilms". Antimicrob Agents Chemother. 2014; 58:5363-7.
de la Fuente-Núñez C, Reffuveille F, Haney EF, Straus SK, Hancock REW. "Broad-spectrum anti-biofilm peptide that targets a cellular stress response". PLoS Pathog. 2014; 10:e1004152.
de la Fuente-Núñez C et al., "Effect of nitroxides on swarming motility and biofilm formation, multicellular behaviors in Pseudomonas aeruginosa". Antimicrob Agents Chemother. 2013; 57:4877-81.