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Infection and Immunity, February 1999, p. 740-744, Vol. 67, No. 2
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Impact of the High-Affinity Proline Permease Gene (putP) on the Virulence of Staphylococcus aureus in Experimental Endocarditis

Arnold S. Bayer,1,2,* Silvija N. Coulter,3 C. Kendall Stover,3 and William R. Schwan3

St. John's Cardiovascular Research Center, Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California 905091; UCLA School of Medicine, Los Angeles, California 900242; and PathoGenesis Corporation, Seattle, Washington 981193

Received 29 May 1998/Returned for modification 28 July 1998/Accepted 10 November 1998

Staphylococcus aureus causes a wide variety of invasive human infections. However, delineation of the genes which are essential for the in vivo survival of this pathogen has not been accomplished to date. Using signature tag mutagenesis techniques and large mutant pool screens, previous investigators identified several major gene classes as candidate essential gene loci for in vivo survival; these include genes for amino acid transporters, oligopeptide transporters, and lantibiotic synthesis (W. R. Schwan, S. N. Coulter, E. Y. W. Ng, M. H. Langhorne, H. D. Ritchie, L. L. Brody, S. Westbrock-Wadman, A. S. Bayer, K. R. Folger, and C. K. Stover, Infect. Immun. 66:567-572, 1998). In this study, we directly compared the virulence of four such isogenic signature tag mutants with that of the parental strain (RN6390) by using a prototypical model of invasive S. aureus infection, experimental endocarditis (IE). The oligonucleotide signature tag (OST) mutant with insertional inactivation of the gene (putP) which encodes the high-affinity transporter for proline uptake exhibited significantly reduced virulence in the IE model across three challenge inocula (104 to 106 CFU) in terms of achievable intravegetation densities (P, <0.05). The negative impact of putP inactivation on in vivo survival in the IE model was confirmed by simultaneous challenge with the original putP mutant and the parental strain as well as by challenge with a putP mutant in which this genetic inactivation was transduced into a distinct parental strain (S6C). In contrast, inactivation of loci encoding an oligopeptide transporter, a purine repressor, and lantibiotic biosynthesis had no substantial impact on the capacity of OST mutants to survive within IE vegetations. Thus, genes encoding the uptake of essential amino acids may well represent novel targets for new drug development. These data also confirm the utility of the OST technique as an important screening methodology for identifying candidate genes as requisite loci for the in vivo survival of S. aureus.

* Corresponding author. Mailing address: Division of Infectious Diseases, Harbor-UCLA Medical Center, St. John's Cardiovascular Research Center, Bldg. RB2, Room 225, 1000 West Carson St., Torrance, CA 90509. Phone: 310-222-6422. Fax: 310-782-2016. E-mail: Bayer{at}HUMC.Edu.

Infection and Immunity, February 1999, p. 740-744, Vol. 67, No. 2
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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