About

John Mekalanos is the Lehman Professor at Harvard Medical School and has served as Chair of the Department of Microbiology and Immunobiology (formerly Microbiology and Molecular Genetics) since 1996. He has received numerous honors including election to the National Academy of Sciences and the American Academy of Microbiology, the Eli Lilly Award, the AAAS Newcomb Cleveland Prize, and the City of Medicine Award. In 2012, he was the first recipient of the Drexel Medicine Prize in Infectious Disease and also received the Sanofi-Institut Pasteur Award for Biomedical Research. Dr. Mekalanos has served on the FDA Advisory Committee on Vaccines and Related Biologics and has consulted for various governmental and private agencies such as the National Institutes of Health, the World Health Organization, The International Vaccine Institute, the National Academy of Sciences, Massachusetts Public Health Biological Laboratories, and the US-Japan Cooperative Medical Science Program. His research focuses on multiple facets of bacterial pathogenesis, emphasizing genetic and functional genomic approaches to explore virulence gene regulation and host-pathogen interactions. His laboratory has developed many genetic tools that have been widely used in the field for decades, establishing fundamentally new approaches to understanding bacterial virulence from the gene to the genomic levels. The Mekalanos group has made classic contributions including identifying regulatory factors controlling cholera toxin and the intestinal colonization factor TCP, discovering the filamentous bacteriophage carrying cholera toxin genes, developing reporters for virulence gene expression in vivo, and identifying small molecules that inhibit virulence. More recently, his laboratory discovered the Type VI secretion system and has made significant progress in defining its dynamic function. Additionally, his group has contributed to the development of prototype vaccines effective against cholera, typhoid, anthrax, and other encapsulated microorganisms, and has provided evidence that bacteriophages control cholera epidemics in natural endemic settings. Dr. Mekalanos has mentored numerous graduate students and postdoctoral fellows, many of whom hold positions at major academic and research institutions worldwide.

Research topics

• Biology
• Microbiology
• Virology
• Cell biology
• Genetics
• Immunology
• Computational biology
• Biochemistry

Selected publications

• Pandemic <scp> <i>Vibrio cholerae</i> </scp> and the Environmental Reservoir Hypothesis—Outstanding Questions Central to Global Cholera Control

  Environmental Microbiology · 2026-04-30

  articleOpen access

  Despite global cholera cases rising to more than 560,000 in 2024, there remains no consensus on a fundamental aspect of cholera epidemiology: whether pandemic Vibrio cholerae forms long-term environmental reservoirs which become the source of future outbreaks. This knowledge gap prevents optimal disease forecasting, resource allocation and outbreak response in a variety of at-risk settings, from places experiencing annual cholera outbreaks (such as the Democratic Republic of the Congo) to those where the disease seemingly reappears after an absence (such as Haiti). Here, we provide a new framework on links between pandemic cholera and ecological parameters, demonstrating a complex and perhaps time-limited relationship between pathogen and environment. The framework in turn illustrates several outstanding questions which can be addressed to better understand whether, when and how environmental reservoirs perpetuate cholera, thereby helping to advance global cholera control.

  PublisherDOI

• Natural directed evolution in gut microbiota

  Science · 2025-10-09 · 1 citations

  articleSenior author

  Bacteria undergo rapid genetic changes that are selected by alterations in the human gut environment.

  PublisherDOI

• A family of lethal exotoxins defined by cell entry via the Attractin receptor

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-08 · 1 citations

  preprintOpen access

  Although bacterial genomes encode numerous potential toxins, it is unclear how evolution drives the specificity of these important virulence factors. Using an insect CRISPR screen, we identified the transmembrane protein Attractin (ATRN) as the receptor for Nigritoxin (Ntx), a Vibrio toxin that causes seasonal shrimp pandemics. We found that Ntx's effector "warhead" inhibits translation via a previously uncharacterized mechanism. Moreover, we show that two related toxins require ATRN for entry but possess unrelated effector domains. One has a Rho-GTPase AMPylation function and the other an actin-targeting/proteolysis function. Our findings reveal the mechanism of Ntx entry and toxicity and show that the ATRN-targeting domain can deliver disparate effector domains, strongly indicating that this class of exotoxins can evolve as modular proteins using a common entry domain.

  PublisherOA PDFDOI

• DdmABC-dependent death triggered by viral palindromic DNA sequences

  Cell Reports · 2024-07-01 · 24 citations

  articleOpen accessSenior authorCorresponding

  Defense systems that recognize viruses provide important insights into both prokaryotic and eukaryotic innate immunity mechanisms. Such systems that restrict foreign DNA or trigger cell death have recently been recognized, but the molecular signals that activate many of these remain largely unknown. Here, we characterize one such system in pandemic Vibrio cholerae responsible for triggering cell density-dependent death (CDD) of cells in response to the presence of certain genetic elements. We show that the key component is the Lamassu DdmABC anti-phage/plasmid defense system. We demonstrate that signals that trigger CDD were palindromic DNA sequences in phages and plasmids that are predicted to form stem-loop hairpins from single-stranded DNA. Our results suggest that agents that damage DNA also trigger DdmABC activation and inhibit cell growth. Thus, any infectious process that results in damaged DNA, particularly during DNA replication, can in theory trigger DNA restriction and death through the DdmABC abortive infection system.

  PublisherDOI

• A coordinated attack by a bacterial secretion system and a small molecule drives prey specificity

  Communications Biology · 2024-08-08 · 5 citations

  articleOpen accessSenior author

  Vibrio species are recognized for their role in food- and water-borne diseases in humans, fish, and aquatic invertebrates. We screened bacterial strains isolated from raw food shrimp for those that are bactericidal to Vibrio strains. Here we identify and characterize Aeromonas dhakensis strain A603 which shows robust bactericidal activity specifically towards Vibrio and related taxa but less potency toward other Gram-negative species. Using the A603 genome and genetic analysis, we show that two antibacterial mechanisms account for its vibriocidal activity -- a highly potent Type Six Secretion System (T6SS) and biosynthesis of a vibriocidal phenazine-like small molecule, named here as Ad-Phen. Further analysis indicates coregulation between Ad-Phen and a pore-forming T6SS effector TseC, which potentiates V. cholerae to killing by Ad-Phen. Bacteria employ the Type 6 Secretion System (T6SS) to kill other bacteria using secreted protein effectors that target cell processes. We show an Aeromonad utilizes both T6SS and a small inhibitory molecule to target specific taxa

  PublisherOA PDFDOI

• Gut complement induced by the microbiota combats pathogens and spares commensals

  Cell · 2024-01-26 · 81 citations

  articleOpen access
  PublisherOA PDFDOI

• Culture of attenuated <i>Salmonella</i> Typhimurium VNP20009 in animal-product-free media does not alter schwannoma growth control

  Human Vaccines & Immunotherapeutics · 2023-08-01 · 1 citations

  articleOpen access

  . Typhimurium serially passaged in animal-product-free media, naming it VNP20009-AF for "VNP20009-animal-product-free." Our in vitro data did not indicate any significant changes in the viability, motility, or morphology of VNP20009-AF, compared to its parental strain. In vivo efficacy data demonstrated that VNP20009-AF and VNP20009 controlled tumor growth to the same degree in both human NF2-schwannoma xenograft and murine-NF2 schwannoma allograft models. Together, these data support the use of VNP20009-AF for the translation of bacterial schwannoma therapy into clinical trials.

  PublisherDOI

• A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonates

  EBioMedicine · 2023-01-27 · 20 citations

  articleOpen access

  BACKGROUND: Worldwide, Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but full understanding of the pathogenesis of this disease is not yet achieved. Moreover, to date, no vaccine is available against bacterial neonatal meningitis. METHODS: Here, we used Transposon Sequencing of saturated banks of mutants (TnSeq) to evaluate E. coli K1 genetic fitness in murine neonatal meningitis. We identified E. coli K1 genes encoding for factors important for systemic dissemination and brain infection, and focused on products with a likely outer-membrane or extra-cellular localization, as these are potential vaccine candidates. We used in vitro and in vivo models to study the efficacy of active and passive immunization. RESULTS: We selected for further study the conserved surface polysaccharide Poly-β-(1-6)-N-Acetyl Glucosamine (PNAG), as a strong candidate for vaccine development. We found that PNAG was a virulence factor in our animal model. We showed that both passive and active immunization successfully prevented and/or treated meningitis caused by E. coli K1 in neonatal mice. We found an excellent opsonophagocytic killing activity of the antibodies to PNAG and in vitro these antibodies were also able to decrease binding, invasion and crossing of E. coli K1 through two blood brain barrier cell lines. Finally, to reinforce the potential of PNAG as a vaccine candidate in bacterial neonatal meningitis, we demonstrated that Group B Streptococcus, the main cause of neonatal meningitis in developed countries, also produced PNAG and that antibodies to PNAG could protect in vitro and in vivo against this major neonatal pathogen. INTERPRETATION: Altogether, these results indicate the utility of a high-throughput DNA sequencing method to identify potential immunotherapy targets for a pathogen, including in this study a potential broad-spectrum target for prevention of neonatal bacterial infections. FUNDINGS: ANR Seq-N-Vaq, Charles Hood Foundation, Hearst Foundation, and Groupe Pasteur Mutualité.

  PublisherOA PDFDOI

• Draft Genome Sequence of Vibrio parahaemolyticus PSU5579, Isolated during an Outbreak of Acute Hepatopancreatic Necrosis Disease in Thailand

  Microbiology Resource Announcements · 2023-01-19 · 3 citations

  articleOpen access

  Here, we announce the draft genome sequence of Vibrio parahaemolyticus strain PSU5579, isolated from a shrimp hatchery in southern Thailand during an outbreak of acute hepatopancreatic necrosis disease (AHPND). The genome contains 44 contigs with a sequence length of 5,229,426 bp, 4,861 coding sequences, and a G+C content of 45.3%.

  PublisherDOI

• Synthetic peptides that form nanostructured micelles have potent antibiotic and antibiofilm activity against polymicrobial infections

  Proceedings of the National Academy of Sciences · 2023-01-17 · 45 citations

  articleOpen access

  The emergence of multidrug-resistant bacterial pathogens is a growing threat to global public health. Here, we report the development and characterization of a panel of nine–amino acid residue synthetic peptides that display potent antibacterial activity and the ability to disrupt preestablished microbial biofilms. The lead peptide (Peptide K6) showed bactericidal activity against Pseudomonas aeruginosa and Staphylococcus aureus in culture and in monocultures and mixed biofilms in vitro. Biophysical analysis revealed that Peptide K6 self-assembled into nanostructured micelles that correlated with its strong antibiofilm activity. When surface displayed on the outer membrane protein LamB, two copies of the Peptide K6 were highly bactericidal to Escherichia coli. Peptide K6 rapidly increased the permeability of bacterial cells, and resistance to this toxic peptide occurred less quickly than that to the potent antibiotic gentamicin. Furthermore, we found that Peptide K6 was safe and effective in clearing mixed P. aeruginosa–S. aureus biofilms in a mouse model of persistent infection. Taken together, the properties of Peptide K6 suggest that it is a promising antibiotic candidate and that design of additional short peptides that form micelles represents a worthwhile approach for the development of antimicrobial agents.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM068851

  NIH · $3.9M · 2017

• NIH Grant R01AI026289

  NIH · $11.5M · 2020

• NIH Grant T32AI007410

  NIH · $1.6M · 2002

• Coordinate Regulation of Virulence in Vibrio Cholerae

  NIH · $17.0M · 1981–2029

• Innovative Platforms for Antimicrobial Therapy and Vaccine Development

  NIH · $50.4M · 2014–2019

Frequent coauthors

• Shah M. Faruque

  Poultry Research Institute

  75 shared

• Matthew K. Waldor

  Howard Hughes Medical Institute

  60 shared

• R. John Collier

  40 shared

• Stephen B. Calderwood

  Massachusetts General Hospital

  39 shared

• Michelle Dziejman

  University of Rochester Medical Center

  35 shared

• Eric J. Rubin

  32 shared

• Joseph D. Mougous

  University of Washington

  29 shared

• Casey A. Gifford

  Stanford University

  29 shared

Labs

• Mekalanos LabPI

  Research on bacterial pathogenesis, focusing on genetic and functional genomic approaches to explore virulence gene regulation and host-pathogen interactions.

Education

• Ph.D.

  University of California Los Angeles