Download PDF
Semin Respir Crit Care Med 2011; 32(2): 228-235
DOI: 10.1055/s-0031-1275535
© Thieme Medical Publishers

Therapies against Virulence Products of Staphylococcus aureus and Pseudomonas aeruginosa

Jeanine P. Wiener-Kronish1 , Jean-Francois Pittet2 , 3 , 4
  • 1Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts
  • 2Department of Anesthesiology, Critical Care Division, University of Alabama at Birmingham, Birmingham, Alabama
  • 3Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
  • 4Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama
Further Information

Publication History

Publication Date:
19 April 2011 (online)

    Permissions and Reprints

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are key pathogens in hospitals (particularly intensive care units), in long-term care facilities, and in outpatients with specific comorbidities and risk factors. Both MRSA and P. aeruginosa display resistance to a wide array of antibiotics. Further, both bacteria contain a variety of virulence products or systems that make it difficult to treat associated infections. Within the past several years, community-acquired MRSA containing virulence factors [particularly the Panton-Valentine leukocidin (PVL) gene] has emerged globally. Given the limited number of novel antibiotics to treat antibiotic-resistant organisms, there is growing interest in treating bacterial infections by targeting specific virulence products or systems. This article reviews potential therapeutic targets in the virulence systems of these two bacteria that are responsible for a large number of serious infections in critically ill patients.

KEYWORDS

Methicillin-resistant S. aureus - Pseudomonas aeruginosa - virulence - antibiotic resistance - Panton-Valentine leukocidin (PVL) gene - toxins - exotoxins

REFERENCES

  • 1 David M Z, Daum R S. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic.  Clin Microbiol Rev. 2010;  23 (3) 616-687
    CrossrefPubMedGoogle Scholar
  • 2 Panlilio A L, Culver D H, Gaynes R P National Nosocomial Infections Surveillance System. et al. Methicillin-resistant Staphylococcus aureus in U.S. hospitals, 1975-1991.  Infect Control Hosp Epidemiol. 1992;  13 (10) 582-586
    CrossrefPubMedGoogle Scholar
  • 3 NNIS System . National Nosocomial Infections Surveillance [NNIS] System Report, data summary from January 1992 through June 2003, issued August 2003.  Am J Infect Control. 2003;  31 (8) 481-498
    CrossrefPubMedGoogle Scholar
  • 4 Chambers H F. The changing epidemiology of Staphylococcus aureus?.  Emerg Infect Dis. 2001;  7 (2) 178-182
    CrossrefPubMedGoogle Scholar
  • 5 Herold B C, Immergluck L C, Maranan M C et al.. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk.  JAMA. 1998;  279 (8) 593-598
    CrossrefPubMedGoogle Scholar
  • 6 Lowy F D. Staphylococcus aureus infections.  N Engl J Med. 1998;  339 (8) 520-532
    CrossrefPubMedGoogle Scholar
  • 7 Troillet N, Carmeli Y, Samore M H et al.. Carriage of methicillin-resistant Staphylococcus aureus at hospital admission.  Infect Control Hosp Epidemiol. 1998;  19 (3) 181-185
    CrossrefPubMedGoogle Scholar
  • 8 Liu C C, Graber C J, Karr M et al.. A population-based study of the incidence and molecular epidemiology of methicillin-resistant Staphylococcus aureus disease in San Francisco, 2004-2005.  Clin Infect Dis. 2008;  46 (11) 1637-1646
    CrossrefPubMedGoogle Scholar
  • 9 Hersh A L, Chambers H F, Maselli J H, Gonzales R. National trends in ambulatory visits and antibiotic prescribing for skin and soft-tissue infections.  Arch Intern Med. 2008;  168 (14) 1585-1591
    CrossrefPubMedGoogle Scholar
  • 10 Kaplan S L, Hulten K G, Gonzalez B E et al.. Three-year surveillance of community-acquired Staphylococcus aureus infections in children.  Clin Infect Dis. 2005;  40 (12) 1785-1791
    CrossrefPubMedGoogle Scholar
  • 11 Klevens R M, Morrison M A, Nadle J Active Bacterial Core surveillance (ABCs) MRSA Investigators et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States.  JAMA. 2007;  298 (15) 1763-1771
    CrossrefPubMedGoogle Scholar
  • 12 Boussaud V, Parrot A, Mayaud C et al.. Life-threatening hemoptysis in adults with community-acquired pneumonia due to Panton-Valentine leukocidin-secreting Staphylococcus aureus.  Intensive Care Med. 2003;  29 (10) 1840-1843
    CrossrefPubMedGoogle Scholar
  • 13 Cribier B, Prévost G, Couppie P, Finck-Barbançon V, Grosshans E, Piémont Y. Staphylococcus aureus leukocidin: a new virulence factor in cutaneous infections? An epidemiological and experimental study.  Dermatology. 1992;  185 (3) 175-180
    CrossrefPubMedGoogle Scholar
  • 14 Adem P V, Montgomery C P, Husain A N et al.. Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children.  N Engl J Med. 2005;  353 (12) 1245-1251
    CrossrefPubMedGoogle Scholar
  • 15 Baba T, Takeuchi F, Kuroda M et al.. Genome and virulence determinants of high virulence community-acquired MRSA.  Lancet. 2002;  359 (9320) 1819-1827
    CrossrefPubMedGoogle Scholar
  • 16 Voyich J M, Otto M, Mathema B et al.. Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease?.  J Infect Dis. 2006;  194 (12) 1761-1770
    CrossrefPubMedGoogle Scholar
  • 17 Bubeck Wardenburg J, Bae T, Otto M, Deleo F R, Schneewind O. Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia.  Nat Med. 2007;  13 (12) 1405-1406
    CrossrefPubMedGoogle Scholar
  • 18 Bubeck Wardenburg J, Palazzolo-Ballance A M, Otto M, Schneewind O, DeLeo F R. Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease. .  J Infect Dis. 2008;  198 (8) 1166-1170
    CrossrefPubMedGoogle Scholar
  • 19 Montgomery C P, Boyle-Vavra S, Adem P V et al.. Comparison of virulence in community-associated methicillin-resistant Staphylococcus aureus pulsotypes USA300 and USA400 in a rat model of pneumonia.  J Infect Dis. 2008;  198 (4) 561-570
    CrossrefPubMedGoogle Scholar
  • 20 Löffler B, Hussain M, Grundmeier M et al.. Staphylococcus aureus panton-valentine leukocidin is a very potent cytotoxic factor for human neutrophils.  PLoS Pathog. 2010;  6 (1) e1000715
    CrossrefPubMedGoogle Scholar
  • 21 Varshney A K, Martinez L R, Hamilton S M et al.. Augmented production of Panton-Valentine leukocidin toxin in methicillin-resistant and methicillin-susceptible Staphylococcus aureus is associated with worse outcome in a murine skin infection model.  J Infect Dis. 2010;  201 (1) 92-96
    CrossrefPubMedGoogle Scholar
  • 22 Goering R V, McDougal L K, Fosheim G E, Bonnstetter K K, Wolter D J, Tenover F C. Epidemiologic distribution of the arginine catabolic mobile element among selected methicillin-resistant and methicillin-susceptible Staphylococcus aureus isolates.  J Clin Microbiol. 2007;  45 (6) 1981-1984
    CrossrefPubMedGoogle Scholar
  • 23 Wang R, Braughton K R, Kretschmer D et al.. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA.  Nat Med. 2007;  13 (12) 1510-1514
    CrossrefPubMedGoogle Scholar
  • 24 Diep B A, Otto M. The role of virulence determinants in community-associated MRSA pathogenesis.  Trends Microbiol. 2008;  16 (8) 361-369
    CrossrefPubMedGoogle Scholar
  • 25 Hongo I, Baba T, Oishi K, Morimoto Y, Ito T, Hiramatsu K. Phenol-soluble modulin alpha 3 enhances the human neutrophil lysis mediated by Panton-Valentine leukocidin.  J Infect Dis. 2009;  200 (5) 715-723
    CrossrefPubMedGoogle Scholar
  • 26 Foster T J. Immune evasion by staphylococci.  Nat Rev Microbiol. 2005;  3 (12) 948-958
    CrossrefPubMedGoogle Scholar
  • 27 Uhlén M B, Guss B, Nilsson B, Gatenbeck S, Philipson L, Lindberg M. Complete sequence of the staphylococcal gene encoding protein A: a gene evolved through multiple duplications.  J Biol Chem. 1984;  259 (3) 1695-1702
    PubMedGoogle Scholar
  • 28 Lorenz U, Lorenz B, Schmitter T et al.. Functional antibodies targeting IsaA of Staphylococcus aureus augment host immune response and open new perspectives for antibacterial therapy.  Antimicrob Agents Chemother. 2011;  55 (1) 165-173
    CrossrefPubMedGoogle Scholar
  • 29 National Nosocomial Infection Surveillance System . National Nosocomial Infection Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004.  Am J Infect Control. 2004;  32 (8) 470-485
    CrossrefPubMedGoogle Scholar
  • 30 El Solh A A, Akinnusi M E, Wiener-Kronish J P, Lynch S V, Pineda L A, Szarpa K. Persistent infection with Pseudomonas aeruginosa in ventilator-associated pneumonia.  Am J Respir Crit Care Med. 2008;  178 (5) 513-519
    CrossrefPubMedGoogle Scholar
  • 31 Chastre J, Wolff M, Fagon J Y PneumA Trial Group et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial.  JAMA. 2003;  290 (19) 2588-2598
    CrossrefPubMedGoogle Scholar
  • 32 Diaz M H, Hauser A R. Pseudomonas aeruginosa cytotoxin ExoU is injected into phagocytic cells during acute pneumonia.  Infect Immun. 2010;  78 (4) 1447-1456
    CrossrefPubMedGoogle Scholar
  • 33 Zhuo H, Yang K, Lynch S V et al.. Increased mortality of ventilated patients with endotracheal Pseudomonas aeruginosa without clinical signs of infection.  Crit Care Med. 2008;  36 (9) 2495-2503
    CrossrefPubMedGoogle Scholar
  • 34 Mastropierro R, Bettinzoli M, Bordonali T, Patroni A, Barni C, Manzato A. Pneumonia in a cardiothoracic intensive care unit: incidence and risk factors.  J Cardiothorac Vasc Anesth. 2009;  23 (6) 780-788
    CrossrefPubMedGoogle Scholar
  • 35 Rangel E L, Butler K L, Johannigman J A, Tsuei B J, Solomkin J S. Risk factors for relapse of ventilator-associated pneumonia in trauma patients.  J Trauma. 2009;  67 (1) 91-95, discussion 95–96
    CrossrefPubMedGoogle Scholar
  • 36 Chenoweth C E, Washer L L, Obeyesekera K et al.. Ventilator-associated pneumonia in the home care setting.  Infect Control Hosp Epidemiol. 2007;  28 (8) 910-915
    CrossrefPubMedGoogle Scholar
  • 37 Yang K, Zhuo H, Guglielmo B J, Wiener-Kronish J P. Multidrug-resistant Pseudomonas aeruginosa ventilator-associated pneumonia: the role of endotracheal aspirate surveillance cultures.  Ann Pharmacother. 2009;  43 (1) 28-35
    CrossrefPubMedGoogle Scholar
  • 38 O'Toole G A, Kolter R. Flagellar and twitching motility are necessary for Pseudomonas aeruginosa biofilm development.  Mol Microbiol. 1998;  30 (2) 295-304
    CrossrefPubMedGoogle Scholar
  • 39 Fleiszig S M, Arora S K, Van R, Ramphal R. FlhA, a component of the flagellum assembly apparatus of Pseudomonas aeruginosa, plays a role in internalization by corneal epithelial cells.  Infect Immun. 2001;  69 (8) 4931-4937
    CrossrefPubMedGoogle Scholar
  • 40 Wolfgang M C, Jyot J, Goodman A L, Ramphal R, Lory S. Pseudomonas aeruginosa regulates flagellin expression as part of a global response to airway fluid from cystic fibrosis patients.  Proc Natl Acad Sci U S A. 2004;  101 (17) 6664-6668
    CrossrefPubMedGoogle Scholar
  • 41 Hahn H P. The type-4 pilus is the major virulence-associated adhesin of Pseudomonas aeruginosa—a review.  Gene. 1997;  192 (1) 99-108
    CrossrefPubMedGoogle Scholar
  • 42 Augustin D K, Song Y, Baek M S et al.. Presence or absence of lipopolysaccharide O antigens affects type III secretion by Pseudomonas aeruginosa.  J Bacteriol. 2007;  189 (6) 2203-2209
    CrossrefPubMedGoogle Scholar
  • 43 Kipnis E, Guery B P, Tournoys A et al.. Massive alveolar thrombin activation in Pseudomonas aeruginosa-induced acute lung injury.  Shock. 2004;  21 (5) 444-451
    CrossrefPubMedGoogle Scholar
  • 44 Bleves S, Viarre V, Salacha R, Michel G P, Filloux A, Voulhoux R. Protein secretion systems in Pseudomonas aeruginosa: a wealth of pathogenic weapons.  Int J Med Microbiol. 2010;  300 (8) 534-543
    CrossrefPubMedGoogle Scholar
  • 45 Hauser A R. The type III secretion system of Pseudomonas aeruginosa: infection by injection.  Nat Rev Microbiol. 2009;  7 (9) 654-665
    CrossrefPubMedGoogle Scholar
  • 46 Berra L, Sampson J, Wiener-Kronish J. Pseudomonas aeruginosa: acute lung injury or ventilator-associated pneumonia?.  Minerva Anestesiol. 2010;  76 (10) 824-832
    PubMedGoogle Scholar
  • 47 Wojciak-Stothard B, Tsang L Y, Haworth S G. Rac and Rho play opposing roles in the regulation of hypoxia/reoxygenation-induced permeability changes in pulmonary artery endothelial cells.  Am J Physiol Lung Cell Mol Physiol. 2005;  288 (4) L749-L760
    PubMedGoogle Scholar
  • 48 Sato H, Feix J B, Frank D W. Identification of superoxide dismutase as a cofactor for the pseudomonas type III toxin, ExoU.  Biochemistry. 2006;  45 (34) 10368-10375
    CrossrefPubMedGoogle Scholar
  • 49 Ganter M T, Roux J, Su G et al.. Role of small GTPases and alphavbeta5 integrin in Pseudomonas aeruginosa-induced increase in lung endothelial permeability.  Am J Respir Cell Mol Biol. 2009;  40 (1) 108-118
    PubMedGoogle Scholar
  • 50 Sayner S L, Frank D W, King J, Chen H, VandeWaa J, Stevens T. Paradoxical cAMP-induced lung endothelial hyperpermeability revealed by Pseudomonas aeruginosa ExoY.  Circ Res. 2004;  95 (2) 196-203
    CrossrefPubMedGoogle Scholar
  • 51 Sayner S L, Alexeyev M, Dessauer C W, Stevens T. Soluble adenylyl cyclase reveals the significance of cAMP compartmentation on pulmonary microvascular endothelial cell barrier.  Circ Res. 2006;  98 (5) 675-681
    CrossrefPubMedGoogle Scholar
  • 52 Winson M K, Camara M, Latifi A et al.. Multiple N-acyl-L-homoserine lactone signal molecules regulate production of virulence determinants and secondary metabolites in Pseudomonas aeruginosa.  Proc Natl Acad Sci U S A. 1995;  92 (20) 9427-9431
    CrossrefPubMedGoogle Scholar
  • 53 Gambello M J, Iglewski B H. Cloning and characterization of the Pseudomonas aeruginosa lasR gene, a transcriptional activator of elastase expression.  J Bacteriol. 1991;  173 (9) 3000-3009
    PubMedGoogle Scholar
  • 54 Pesci E C, Milbank J B, Pearson J P et al.. Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa.  Proc Natl Acad Sci U S A. 1999;  96 (20) 11229-11234
    CrossrefPubMedGoogle Scholar
  • 55 Mah T F, Pitts B, Pellock B, Walker G C, Stewart P S, O'Toole G A. A genetic basis for Pseudomonas aeruginosa biofilm antibiotic resistance.  Nature. 2003;  426 (6964) 306-310
    CrossrefPubMedGoogle Scholar
  • 56 Flanagan J L, Brodie E L, Weng L et al.. Loss of bacterial diversity during antibiotic treatment of intubated patients colonized with Pseudomonas aeruginosa.  J Clin Microbiol. 2007;  45 (6) 1954-1962
    CrossrefPubMedGoogle Scholar
  • 57 Sawa T, Yahr T L, Ohara M et al.. Active and passive immunization with the Pseudomonas V antigen protects against type III intoxication and lung injury.  Nat Med. 1999;  5 (4) 392-398
    CrossrefPubMedGoogle Scholar
  • 58 Neely A N, Holder I A, Wiener-Kronish J P, Sawa T. Passive anti-PcrV treatment protects burned mice against Pseudomonas aeruginosa challenge.  Burns. 2005;  31 (2) 153-158
    CrossrefPubMedGoogle Scholar
  • 59 Baer M, Sawa T, Flynn P et al.. An engineered human antibody fab fragment specific for Pseudomonas aeruginosa PcrV antigen has potent antibacterial activity.  Infect Immun. 2009;  77 (3) 1083-1090
    CrossrefPubMedGoogle Scholar
  • 60 Arnoldo A, Curak J, Kittanakom S et al.. Identification of small molecule inhibitors of Pseudomonas aeruginosa exoenzyme S using a yeast phenotypic screen.  PLoS Genet. 2008;  4 (2) e1000005 [Erratum in: PLoS Genet. 2008 Apr;4(4). doi: 10.1371/annotation/76d35829-07a2-479f-bbc1-cce6755b6d8c. Merrill, Rod A corrected to Merrill, A Rod]
    CrossrefPubMedGoogle Scholar
  • 61 Bir N, Lafargue M, Howard M et al.. Cytoprotective-selective activated Protein C attenuates P. aeruginosa-induced lung injury in mice.  Am J Respir Mol Cell Biol. 2011 January 21;  [Epub ahead of print]
    PubMedGoogle Scholar

Jeanine P Wiener-KronishM.D. 

Department of Anesthesia and Critical Care, Massachusetts General Hospital

GRB 444, Boston, MA 02114

Email: jwiener-kronish@partners.org