Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Bacteria or actinomycetales; media therefor
Patent
1995-03-15
2000-05-16
Railey, II, Johnny F.
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
Bacteria or actinomycetales; media therefor
435 32, C12N 120, C12Q 118
Patent
active
060636130
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the identification of auxiliary genes that encode proteins involved in antibiotic resistance in bacteria, and to compounds that can antagonize the activity of such proteins, thereby resensitizing resistant bacteria to antibiotics.
BACKGROUND OF THE INVENTION
Clinical-Epidemiological Background
Methicillin resistant strains of Staphylococcus aureus (MRSA) have become first ranking nosocomial pathogens worldwide. These bacteria are responsible for over 40% of all hospital-born staphylococcal infections in large teaching hospitals in the U.S. Most recently they have become prevalent in smaller hospitals (20% incidence in hospitals with 200 to 500 beds), as well as in nursing homes (Wenzel et al., 1992, Am. J. Med. 91(Supp 3B):221-7). An unusual and most unfortunate property of MRSA strains is their ability to pick up additional resistance factors which suppress the susceptibility of these strains to other, chemotherapeutically useful antibiotics. Such multiresistant strains of bacteria are now prevalent all over the world and the most "advanced" forms of these pathogens carry resistance mechanisms to all but one (vancomycin) of the usable antibacterial agents (Blumberg et al., 1991, J. Inf. Disease (63:1279-85).
A most ominous and recent development is the appearance of a vancomycin resistance mechanism in another nosocomial pathogen--Enterococcus faecium--which is known for its ability to transfer from one cell to another plasmid-born resistance factors, such as vancomycin resistance. The arrival of vancomycin resistance to MRSA is only a matter of time. Once this happens, an invasive bacterial pathogen without any antibacterial agent to control it will result. This event would constitute nothing short of a potential public health disaster of immense proportion (Leclercg et al., 1988, New Eng. J. Med. 319:157-61).
The preceding explains the intense interest in the public health and pharmacological community in any new method that promises a usable intervention against MRSA. A more complete explanation of the basis for antibiotic resistance follows.
Molecular Basis of Antibiotic Resistance
The central genetic element of methicillin resistance is the so called mecA gene. This gene is found on a piece of DNA of unknown, non-staphylococcal origin that the ancestral MRSA cell(s) must have acquired from a foreign source. The mecA gene encodes for a penicillin binding protein (PBP) called PBP2A (Murakami and Tomasz, 1989, J. Bacteriol. 171:874-79), which has very low affinity for the entire family of beta lactam antibiotics. In the current view, PBP2A is a kind of "surrogate" cell wall synthesizing enzyme that can take over the vital task of cell wall synthesis in staphylococci when the normal complement of PBPs (the normal catalysts of wall synthesis) can no longer function because thy have become fully inactivated by beta lactam antibiotic in the environment. The critical nature of the mecA gene and its gene product PBP2A for the antibiotic resistant phenotype was best demonstrated by transposon inactivation experiments in which the transposon Tn551 was maneuvered into the mecA gene. The result was a dramatic drop in resistance level from the minimum inhibitory concentration (MIC) value of 1600 .mu.g/ml in the parental bacterium to the low value of about 4 .mu.g/ml in the transposon mutant (Matthews and Tomasz, 1990, Antimicrobial Agents and Chemotherapy 34:1777-9).
This observation is consistent with the foregoing theory. The mutant bacteria with their interrupted mecA gene could no longer synthesize PBP2A; thus the surrogate enzyme needed for the survival in the antibiotic-rich environment was no longer available to catalyze wall synthesis. Consequently, the methicillin susceptibility of the Tn551 mutant dropped to a level approaching the susceptibility of staphylococci without the mecA gene. Methicillin MIC for such bacteria is usually in the vicinity of 1-2 .mu.g/ml.
Auxiliary Genes
Additional genetic work resulted in several surprising obse
REFERENCES:
Berger-Bachi (1994) Trends in Microbiol. 2:389-92.
De Lencastre et al. (1994) Antimicrob. Agent. Chemother. 38:2590-8.
De Lencastre et al. (1994) Eur. J. Clin. Microbiol. Infect. Dis. 13:64-73.
De Lencastre et al. (1994) J. Antimicrob. Chemother. 33:7-24.
Ornelas-Soares et al. (1994) J. Biol. Chem. 269:27246-50.
De Jonge et al. (1993) Animicrob. Agents Chemother. 37:342-6.
De Jonge et al. (1993) J. Bacteriol. 1751:2779-82.
Gustafson et al. (1993) In: Abstracts of the 93rd General Meeting of the American Society for Microbiology, Abs. A-97, p.18.
Henze et al. (1993) J. Bacteriol. 175:1612-20.
Ornelas-Soares et al. (1993) J. Biol. Chem. 268:26268-72.
Berger-Bachi et al. (1992) Antimicrob. Agents Chemotherapy 36:1367-73.
De Jonge et al. (1992) J. Biol. Chem. 267:11248-54.
De Jonge et al. (1992) J. Biol. Chem. 267:11255-9.
Oshida et al. (1992) J. Bacteriol. 174:4952-9.
De Jonge et al. (1991) J. Bacteriol. 173:1105-10.
De Lencastre et al. (1991) Animicrob. Agents Chemother. 35:632-9.
Maidhof et al. (1991) J. Bacteriol. 173:3507-13.
Tomasz et al. (1991) Antimicrobial Agents and Chemotherapy 35:124-9.
Matthews et al. (1990) Antimicrobial Agents and Chemotherapy 34:1777-9.
Tomasz, (1990) In: Molecular Biology of the Staphylococci, Novick and Skurray, Eds., VHC Publishers: New York, pp. 565-583.
Murakami et al. (1989) J. Bacteriol. 171:874-9.
Leclercg et al. (1988) New Eng. J. Med. 319:157-61.
Hartman et al. (1986) Antimicrob. Agent. Chemother. 29:85-92.
Beck et al. (1985) J. Bacteriol. 165:373-8.
Berger-Bachi (1983) J. Bacteriol. 154:479-87.
De Lencastre Herminia
Tomasz Alexander
Railey II Johnny F.
The Rockefeller University
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