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Journal of Clinical Microbiology, November 2008, p. 3863-3865, Vol. 46, No. 11
0095-1137/08/$08.00+0     doi:10.1128/JCM.01081-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Inactivating Methicillin-Resistant Staphylococcus aureus and Other Pathogens by Use of Bacteriocins OR-7 and E 50-52{triangledown}


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LETTER
 
Worldwide, dramatic numbers of reports document the increasing frequency of methicillin-resistant Staphylococcus aureus (MRSA) infections. Other clinically significant human pathogens are increasingly recognized as unresponsive to therapeutic antibiotics of last resort. These previously treatable infections now account for unfortunate numbers of human disease and deaths following severe surface wounds or exposure to nosocomial sources. The inexorable and inextricable expansion of antibiotic-resistant pathogens requires a new and viable response. This report documents a novel set of bacteriocins capable of inactivating MRSA and other refractile, antibiotic-resistant infectious bacteria.

Bacteriocin E 50-52 was produced and purified from Enterococcus faecium NRRL B-30746 according to procedures described previously (4). The bacteriocin OR-7 was produced and purified from Lactobacillus salivarius NRRL B-30514 as described previously (3). The MICs of bacteriocins OR-7, E 50-52, and nisin (commercially available bacteriocin) and 20 selected antibiotics were determined in two independent replicated experiments using a previously described assay (1). Twofold dilutions of pure bacteriocin and antibiotic preparations were mixed with the test organisms (105 CFU/ml) in Mueller-Hinton broth (HiMedia, Mumbai, India), which was incubated aerobically at 37°C for 24 h. Fifteen clinical isolates, identified as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Acinetobacter baumanii, and Proteus spp., were tested (Table 1). The isolates were stored in the State Research Center for Applied Microbiology and Biotechnology laboratory under lyophilized conditions. These human isolates were selected because of their diverse infections and per indicated antibiotic resistance patterns.


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  		TABLE 1. Susceptibilities among human clinical bacteria resistant to selected antibiotics versus MICs of selected bacteriocins

In general, antibiotics target bacterial cell walls or protein/DNA biosynthesis. Cationic nisin may bind to the cell wall or docking molecules, resulting in cell wall disruption and cytoplasmic leakage. The bactericidal mechanism of antibiotics such as ampicillin, methicillin, oxacillin, and penicillin is mediated by a breakdown in cell wall production via the antibiotic-specific β-lactam. Resistance of bacterial strains to the antibiotic is generally via the specific β-lactamase enzymes. Ciprofloxacin, a fluoroquinolone, is frequently considered by clinicians to be an alternative antibiotic of last resort and employs a substantially different mechanism of bacterial inactivation. The fluoroquinolones inhibit bacterial replication at the subcellular DNA gyrase site and are frequently used to treat Staphylococcus aureus infections. Vancomycin is also considered to be a therapeutic antibiotic of last resort in systemic infections.

The clinical isolates used in this study were highly resistant (generally having MICs greater than 4 µg/ml) to the large array of antibiotics tested (Table 1). Selected isolates of C. freundii, K. pneumoniae, Proteus spp., and E. coli were relatively susceptible to meropenem but were highly resistant to the other antibiotics tested. All MRSA S. aureus isolates tested were sensitive to 1 µg/ml of vancomycin. A substantial range of antibiotic classes was employed in the present study. The extreme resistance patterns among these selected clinical isolates were associated with the failed treatment outcomes. Nisin was tested since it is FDA approved and was originally developed to control gram-positive pathogens in processed foods. The MICs of nisin for S. aureus were generally lower than those of the antibiotics tested, but nisin was ineffective against the wide panorama of pathogens we tested. By comparison, bacteriocins OR-7 and E 50-52 had multibacterial bactericidal activities. The MICs of E 50-52 were at least an order of magnitude less than those recorded for OR-7. Both of these bacteriocins were quite effective against all the tested isolates.

Use of the bacteriocin OR-7 as a therapeutic treatment with a chicken intestinal tract colonization model reduced Campylobacter jejuni by one millionfold (3). In a similar model, bacteriocin E 50-52 treatment reduced systemic Salmonella enteritidis by 100,000-fold in the liver and spleen (4). In a mouse macrophage model for Mycobacterium tuberculosis lung infection (2), aerosol administration of liposome-packaged bacteriocins significantly prolonged the duration of mouse survival. These results reflect the earliest phases of in vivo experimentation and suggest greater applications for bacteriocins in treating infections.

Clearly, alternative and novel treatment regimens are required to address the growing threat of antimicrobial-resistant pathogens. Bacteriocins may play a role as part of a nonantibiotic cyclic rotation with antibiotics and merit further study. Bacteriocins hold the potential to employ antimicrobial therapies with bactericidal outcomes differing dramatically from those of traditional antibiotic regimens.


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FOOTNOTES
 
{triangledown} Published ahead of print on 3 September 2008. Back


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REFERENCES
 
    1
  1. National Committee for Clinical Laboratory Standards. 2000. Performance standards for antimicrobial susceptibility tests, 7th ed. Approved standard, NCCLS document M2-A7, vol 20, issue 1. National Committee for Clinical Laboratory Standards, Wayne, PA.
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  2. Sosunov, V., V. Mischenko, B. Eruslanov, E. Svetoch, Y. Shakina, N. Stern, K. Majorov, G. Sorokoumova, A. Selishcheva, and A. Apt. 2007. Antimycobacterial activity of bacteriocins and their complexes with liposomes. J. Antimicrob. Chemother. 59:919-925.[Abstract/Free Full Text]
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  3. Stern, N. J., E. A. Svetoch, B. V. Eruslanov, V. V. Perelygin, E. V. Mitsevich, I. P. Mitsevich, V. D. Pokhilenko, V. P. Levchuk, O. E. Svetoch, and B. S. Seal. 2006. Isolation of a Lactobacillus salivarius strain and purification of its bacteriocin, which is inhibitory to Campylobacter jejuni in the chicken gastrointestinal system. Antimicrob. Agents Chemother. 50:3111-3116.[Abstract/Free Full Text]
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  4. Svetoch, E. A., B. V. Eruslanov, V. V. Perelygin, E. V. Mitsevich, I. P. Mitsevich, V. N. Borzenkov, V. P. Levchuk, O. E. Svetoch, Y. N. Kovalev, Y. G. Stepanshin, G. R. Siragusa, B. S. Seal, and N. J. Stern. 2008. Diverse antimicrobial killing by Enterococcus faecium E 50-52 bacteriocin. J. Agric. Food Chem. 56:1942-1948.[CrossRef][Medline]
Edward A. Svetoch
Vladimir P. Levchuk
Victor D. Pokhilenko
Boris V. Eruslanov
Evgenii V. Mitsevich
Irina P. Mitsevich
Vladimir V. Perelygin
Yuri G. Stepanshin
State Research Center for Applied Microbiology and Biotechnology (SRCAMB)
Obolensk, Russian Federation

Norman J. Stern*
U.S. Department of Agriculture
Agricultural Research Service (USDA-ARS)
950 College Station Rd.
Russell Research Center
Athens, Georgia 30604

* Phone: (706) 546-3516, Fax: (706) 546-3771, E-mail: norman.stern{at}ars.usda.gov

Journal of Clinical Microbiology, November 2008, p. 3863-3865, Vol. 46, No. 11
0095-1137/08/$08.00+0     doi:10.1128/JCM.01081-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.




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