Therapies against Virulence Products of Staphylococcus aureus and Pseudomonas aeruginosa

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
• 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
• 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
• 4 Chambers H F. The changing epidemiology of Staphylococcus aureus?.  Emerg Infect Dis. 2001;  7 (2) 178-182
• 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
• 6 Lowy F D. Staphylococcus aureus infections.  N Engl J Med. 1998;  339 (8) 520-532
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 24 Diep B A, Otto M. The role of virulence determinants in community-associated MRSA pathogenesis.  Trends Microbiol. 2008;  16 (8) 361-369
• 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
• 26 Foster T J. Immune evasion by staphylococci.  Nat Rev Microbiol. 2005;  3 (12) 948-958
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 45 Hauser A R. The type III secretion system of Pseudomonas aeruginosa: infection by injection.  Nat Rev Microbiol. 2009;  7 (9) 654-665
• 46 Berra L, Sampson J, Wiener-Kronish J. Pseudomonas aeruginosa: acute lung injury or ventilator-associated pneumonia?.  Minerva Anestesiol. 2010;  76 (10) 824-832
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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]
• 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]