Design of Live Attenuated Bacterial Vaccines Based on D-glutamate Auxotrophy

Overview

Journal Nat Commun

Specialty Biology

Date 2017 May 27

PMID 28548079

Citations 33

Authors

Maria P Cabral

Patricia Garcia

Alejandro Beceiro

Carlos Rumbo

Astrid Perez

Miriam Moscoso

German Bou

Affiliations

Soon will be listed here.

Abstract

Vaccine development is a priority for global health due to the growing multidrug resistance in bacteria. D-glutamate synthesis is essential for bacterial cell wall formation. Here we present a strategy for generating effective bacterial whole-cell vaccines auxotrophic for D-glutamate. We apply this strategy to generate D-glutamate auxotrophic vaccines for three major pathogens, Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus. These bacterial vaccines show virulence attenuation and self-limited growth in mice, and elicit functional and cross-reactive antibodies, and cellular immunity. These responses correlate with protection against acute lethal infection with other strains of the same species, including multidrug resistant, virulent and/or high-risk clones such as A. baumannii AbH12O-A2 and Ab307-0294, P. aeruginosa PA14, and community-acquired methicillin-resistant S. aureus USA300LAC. This approach can potentially be applied for the development of live-attenuated vaccines for virtually any other bacterial pathogens, and does not require the identification of virulence determinants, which are often pathogen-specific.

Citing Articles

Vaccine Development: Lessons, Challenges, and Future Innovations.

Santamarina-Fernandez R, Fuentes-Valverde V, Silva-Rodriguez A, Garcia P, Moscoso M, Bou G Int J Mol Sci. 2025; 26(5).

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Regulation of antibiotic persistence and pathogenesis in Acinetobacter baumannii by glutamate and histidine metabolic pathways.

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References

Proctor R . Recent developments for Staphylococcus aureus vaccines: clinical and basic science challenges. Eur Cell Mater. 2015; 30:315-26. DOI: 10.22203/ecm.v030a22. View

. A Call for Greater Consideration for the Role of Vaccines in National Strategies to Combat Antibiotic-Resistant Bacteria: Recommendations from the National Vaccine Advisory Committee: Approved by the National Vaccine Advisory Committee on June 10,.... Public Health Rep. 2016; 131(1):11-6. PMC: 4716466. View

Missiakas D, Schneewind O . Staphylococcus aureus vaccines: Deviating from the carol. J Exp Med. 2016; 213(9):1645-53. PMC: 4995089. DOI: 10.1084/jem.20160569. View

Fisher S . Glutamate racemase as a target for drug discovery. Microb Biotechnol. 2011; 1(5):345-60. PMC: 3815242. DOI: 10.1111/j.1751-7915.2008.00031.x. View

Sharma A, Krause A, Worgall S . Recent developments for Pseudomonas vaccines. Hum Vaccin. 2011; 7(10):999-1011. PMC: 3360073. DOI: 10.4161/hv.7.10.16369. View

Jackson M, Phalen S, Lagranderie M, Ensergueix D, Chavarot P, Marchal G . Persistence and protective efficacy of a Mycobacterium tuberculosis auxotroph vaccine. Infect Immun. 1999; 67(6):2867-73. PMC: 96594. DOI: 10.1128/IAI.67.6.2867-2873.1999. View

Smith M, Gianoulis T, Pukatzki S, Mekalanos J, Ornston L, Gerstein M . New insights into Acinetobacter baumannii pathogenesis revealed by high-density pyrosequencing and transposon mutagenesis. Genes Dev. 2007; 21(5):601-14. PMC: 1820901. DOI: 10.1101/gad.1510307. View

Michael A, Geier E, Konshtok R, HERTMAN I, MARKENSON J . Attenutated live fowl cholera vaccine. III. Laboratory and field vaccination trials in turkeys and chickens. Avian Dis. 1979; 23(4):878-85. View

Liu J, Tran V, Leung A, Alexander D, Zhu B . BCG vaccines: their mechanisms of attenuation and impact on safety and protective efficacy. Hum Vaccin. 2009; 5(2):70-8. DOI: 10.4161/hv.5.2.7210. View

10.

Scully I, Liberator P, Jansen K, Anderson A . Covering all the Bases: Preclinical Development of an Effective Staphylococcus aureus Vaccine. Front Immunol. 2014; 5:109. PMC: 3970019. DOI: 10.3389/fimmu.2014.00109. View

11.

Middleton J . Staphylococcus aureus antigens and challenges in vaccine development. Expert Rev Vaccines. 2008; 7(6):805-15. DOI: 10.1586/14760584.7.6.805. View

12.

Schleifer K, Kandler O . Peptidoglycan types of bacterial cell walls and their taxonomic implications. Bacteriol Rev. 1972; 36(4):407-77. PMC: 408328. DOI: 10.1128/br.36.4.407-477.1972. View

13.

Giersing B, Dastgheyb S, Modjarrad K, Moorthy V . Status of vaccine research and development of vaccines for Staphylococcus aureus. Vaccine. 2016; 34(26):2962-2966. DOI: 10.1016/j.vaccine.2016.03.110. View

14.

Zhao Y, Nilsson I, Tarkowski A . The dual role of interferon-gamma in experimental Staphylococcus aureus septicaemia versus arthritis. Immunology. 1998; 93(1):80-5. PMC: 1364109. DOI: 10.1046/j.1365-2567.1998.00407.x. View

15.

Curtiss 3rd R . Bacterial infectious disease control by vaccine development. J Clin Invest. 2002; 110(8):1061-6. PMC: 150804. DOI: 10.1172/JCI16941. View

16.

Arnaud M, Chastanet A, Debarbouille M . New vector for efficient allelic replacement in naturally nontransformable, low-GC-content, gram-positive bacteria. Appl Environ Microbiol. 2004; 70(11):6887-91. PMC: 525206. DOI: 10.1128/AEM.70.11.6887-6891.2004. View

17.

Garcia-Quintanilla M, Pulido M, Pachon J, McConnell M . Immunization with lipopolysaccharide-deficient whole cells provides protective immunity in an experimental mouse model of Acinetobacter baumannii infection. PLoS One. 2014; 9(12):e114410. PMC: 4259314. DOI: 10.1371/journal.pone.0114410. View

18.

Spellberg B, Ibrahim A, Yeaman M, Lin L, Fu Y, Avanesian V . The antifungal vaccine derived from the recombinant N terminus of Als3p protects mice against the bacterium Staphylococcus aureus. Infect Immun. 2008; 76(10):4574-80. PMC: 2546811. DOI: 10.1128/IAI.00700-08. View

19.

Brown A, Murphy A, Lalor S, Leech J, OKeeffe K, Mac Aogain M . Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection. PLoS Pathog. 2015; 11(11):e1005226. PMC: 4634925. DOI: 10.1371/journal.ppat.1005226. View

20.

Priebe G, Meluleni G, Coleman F, Goldberg J, Pier G . Protection against fatal Pseudomonas aeruginosa pneumonia in mice after nasal immunization with a live, attenuated aroA deletion mutant. Infect Immun. 2003; 71(3):1453-61. PMC: 148856. DOI: 10.1128/IAI.71.3.1453-1461.2003. View