Monoclonal antibody anti-PBP2a protects mice against MRSA (methicillin-resistant Staphylococcus aureus) infections


Autoři: Felipe Betoni Saraiva aff001;  Ana Caroline Cavalcante de Araújo aff001;  Anna Érika Vieira de Araújo aff001;  José Procópio Moreno Senna aff001
Působiště autorů: Instituto de Tecnologia em Imunobiológicos – BioManguinhos – FIOCRUZ, Rio de Janeiro, Brazil aff001
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225752

Souhrn

Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant bacterium responsible for serious nosocomial and community-acquired infections worldwide. Since few antibiotics are effective for treating MRSA infections, the development of new therapies is of great importance. Previous studies demonstrated that PBP2a is a target that generates protective antibodies against MRSA. A murine monoclonal antibody (MAb) that recognizes PBP2a from MRSA strains was previously isolated and characterized. In this report, we evaluated the biodistribution of this MAb in blood and tissues, as well as the extent of protection conferred using prophylactic and therapeutic assays compared to vancomycin treatment. Biodistribution was evaluated 12–96 h after MAb administration. It predominantly remained in the serum, but it was also detectable in the kidneys, lungs, and spleen at low concentrations (about 4.5% in the kidneys, 1.9% in the lungs, and 0.7% the spleen) at all observed timepoints. Prophylactic studies in a murine model demonstrated a significant bacterial load reduction in the kidneys of the groups treated with either with IgG (greater than 3 logs) or F(ab’)2 (98%) when compared to that of the control groups (untreated). Mice were challenged with a lethal dose, and the survival rate was higher in the treated mice. Treatment with the MAb resulted in a bacterial load reduction in the kidneys similar to that of mice treated with vancomycin, and a MAb/vancomycin combination therapy was also effective. These results demonstrate that an anti-PBP2a MAb may be a promising therapeutic for treating MRSA infections.

Klíčová slova:

Antibiotics – Antibodies – Kidneys – Methicillin-resistant Staphylococcus aureus – Mouse models – Vancomycin – Bacterial lethality


Zdroje

1. O’Neil J. Review on antibiotic resistance. Tackling drug resistance globally. 2016; WHO.

2. Ryffel C, Strassle A, Kayser FH, Berger-Bächi B. Mechanisms of heteroresistance in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1994; 38:724–728. doi: 10.1128/aac.38.4.724 8031036

3. Gardete S, Tomasz A. Mechanisms of vancomycin resistance in Staphylococcus aureus. J Clin Invest. 2014;124:2836–2840. doi: 10.1172/JCI68834 24983424

4. Casadevall A. The third age of antimicrobial therapy. Clin Infect Dis. 2006; 42:1414–1416. doi: 10.1086/503431 16619153

5. DiGiandomenico A, Sellman BR. Antibacterial monoclonal antibodies: The next generation? Curr Op in Microbiol. 2015; 27:78–85.

6. Weisman LE, Thackray HM, Garcia-Prats JA, Nesin M, Schneider JH, Fretz J, et al. Phase 1/2 double-bind, placebo controlled, dose escalation, safety and pharmacokinetic study of pagibaxiMAb, an antistaphylococcal monoclonal antibody for the prevention of staphylococcal bloodstream infections, in very-low-birth-weight neonates. Antimicrob Agents and Chemother. 2009; 53:2879–2886.

7. Ragle BE, Bubeck WJ. Anti-alpha-hemolysin monoclonal antibodies mediate protection against Staphylococcus aureus pneumonia. Infect Imm. 2009; 77:2712–2718.

8. Hall AE, Domanski PJ, Patel PR, Vernachio JH, Syribeys PJ, Gorovits EL, et al. Characterization of a protective monoclonal antibody recognizing Staphylococcus aureus MSCRAMM protein clumping factor A. Infect Imm. 2003; 71:6864–6870.

9. Kim HK, Cheng AG, Kim HY, Missiakas DM and Schneewind O. Non toxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections in mice. J Exp Med. 2010; 207(9):1863–1870. doi: 10.1084/jem.20092514 20713595

10. Goffin C, Ghuysen JM. Multimodular penicillin binding proteins: An enigmatic family of orthologs and paralogs. Microbiol Mol Biol Rev. 1998; 62:1079–1093. 9841666

11. Senna JP, Roth DM, Oliveira JS, Machado DC, Santos DS. Protective immune response against methicillin resistant Staphylococcus aureus in a murine model using a DNA vaccine approach. Vaccine. 2003; 21:2661–2666. doi: 10.1016/s0264-410x(02)00738-7 12744903

12. Ohwada A, Sekiya M, Hanaki H, Arai KK, Nagaoka I, Hori S, et al. DNA vaccination by mecA sequence evokes an antibacterial immune response against methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 1999; 44:767–774. doi: 10.1093/jac/44.6.767 10590277

13. Senna JP, Teixeira M da G, Santiago M de A, Batoréu NM, Valadares N, Galler R. Generation and characterization of murine monoclonal antibodies anti-PBP2a of methicillin-resistant Staphylococcus aureus. Monoclon Antib Imunodiagn Immunother. 2015; 34:257–262.

14. Araujo AEV., Souza NP, Souza APB, Senna JPM. Production and characterization of F(Ab’)2 fragments obtained by enzymatic digestion from murine anti-MRSA PBP2a monoclonal antibodies. Appl Biochem Biotechnol. 2016; 185:72–80.

15. Enright MC, Robinson DA, Randle G, Feil EJ, Grundman H and Spratt BG. The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). PNAS. 2002. 99(11): 7687–7692. doi: 10.1073/pnas.122108599 12032344

16. Costa MO, Beltrame CO, Ferreira FA, Botelho AM, Lima NC, Souza RC, et al. Complete genome sequence of a variant of the methicillin-resistant Staphylococcus aureus ST239 lineage, strain BMB9393, displaying superior ability to accumulate ica-independent biofilm. Genome Announc. 2013; 1:pii: e00576–13.

17. Araujo AEV, dos Santos IB, Freire IM, Bonin RF, Machado LA, Senna JPM. Determination of lethal and sublethal doses of Acinetobacter baumannii and Methicillin-resistant Staphylococcus aureus (MRSA) in murine models using a reduced number of animals. J Exp Appl Animal Sci. 2015; 3:336–340.

18. Papakyriacou H, Vaz D, Simor A, Louie M, McGavin MJ. Molecular analysis of the accessory gene regulator (agr) locus and balance of virulence factor expression in epidemic methicillin-resistant Staphylococcus aureus. J Infec Dis. 2000; 181:2400–2404.

19. Naghshbandi RZ, Haghighat S, Mahdavi M. Passive immunization against methicillin resistant Staphylococcus aureus recombinant PBP2a in sepsis model of mice: Comparable results with antibiotic therapy. Int Immunopharmacol. 2018; 56:186–192. doi: 10.1016/j.intimp.2018.01.035 29414649

20. Shah DK, Betts AM. Antibody biodistribution coefficients: inferring tissue concentrations of monoclonal antibodies bases on the plasma concentrations in several preclinical species and human. 2013; MAbs 5:297–305. doi: 10.4161/mabs.23684 23406896


Článek vyšel v časopise

PLOS One


2019 Číslo 11