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Antimicrobial Agents and Chemotherapy, February 2007, p. 475-482, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00786-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Lysostaphin-Resistant Variants of Staphylococcus aureus Demonstrate Reduced Fitness In Vitro and In Vivo{triangledown}

Caroline Kusuma,{dagger} Anna Jadanova,{ddagger} Tanya Chanturiya,§ and John F. Kokai-Kun*

Biosynexus Incorporated, Gaithersburg, Maryland 20877

Received 29 June 2006/ Returned for modification 1 August 2006/ Accepted 31 October 2006

Lysostaphin is under development as a therapy for serious staphylococcal infections. During preclinical development, lysostaphin-resistant Staphylococcus aureus variants have occasionally been reported in vitro and in vivo. The acquisition of resistance to this drug, however, leads to a significant increase in ß-lactam antibiotic susceptibility, rendering methicillin-resistant S. aureus (MRSA) strains functionally methicillin susceptible. In this study, we have demonstrated that the development of lysostaphin resistance by two strains of MRSA also led to a loss of fitness in the variants. Consistent with the mutations found in previously reported lysostaphin-resistant S. aureus variants, these two variants had mutations in their femA genes, resulting in nonfunctional FemA proteins and, thus, monoglycine cross bridges in the peptidoglycan. The diminished fitness of the lysostaphin-resistant variants was reflected by (i) a reduced logarithmic growth rate, with the variants being outcompeted in cocultures by their wild-type parental strains; (ii) increased susceptibility to elevated temperatures; and (iii) at least fivefold less virulence of the lysostaphin-resistant variants than their wild-type strains in a mouse kidney infection model, with the lysostaphin-resistant variants being outcompeted in coinfections with their wild-type parental strains. During a 14-day serial passage without selective pressure, the lysostaphin-resistant variants failed to develop compensatory mutations which restored their fitness. These results suggest that should lysostaphin resistance due to an alteration in the FemA function emerge in S. aureus during therapy with lysostaphin, the resistant variants would be less fit and less virulent, and, in addition, infections with these strains would be easily treatable with ß-lactam antibiotics.

* Corresponding author. Mailing address: Biosynexus Incorporated, 9119 Gaither Rd., Gaithersburg, MD 20877. Phone: (301) 987-1172. Fax: (301) 990-4990. E-mail: johnkun{at}biosynexus.com.

{triangledown} Published ahead of print on 13 November 2006.

{dagger} Present address: AFG Biosolutions, Gaithersburg, MD.

{ddagger} Present address: Hofstra University, Long Island, NY.

§ Present address: National Institutes of Health, Bethesda, MD.

Antimicrobial Agents and Chemotherapy, February 2007, p. 475-482, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00786-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kokai-Kun, J. F., Chanturiya, T., Mond, J. J. (2009). Lysostaphin eradicates established Staphylococcus aureus biofilms in jugular vein catheterized mice. J Antimicrob Chemother 64: 94-100 [Abstract] [Full Text]  
  • Balsalobre, L., de la Campa, A. G. (2008). Fitness of Streptococcus pneumoniae Fluoroquinolone-Resistant Strains with Topoisomerase IV Recombinant Genes. Antimicrob. Agents Chemother. 52: 822-830 [Abstract] [Full Text]  
  • Kokai-Kun, J. F., Chanturiya, T., Mond, J. J. (2007). Lysostaphin as a treatment for systemic Staphylococcus aureus infection in a mouse model. J Antimicrob Chemother 60: 1051-1059 [Abstract] [Full Text]  


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