Structural Studies Towards the Selective Inhibition of the MRSA active Aminoglycoside Modifying Enzyme AAC[6']
Bisubstrate mimics have been designed for some aminoglycoside modifying enzymes and shown to reverse antimicrobial resistance, we seek to emulate this for the enzyme acting in methicillin resistant Staphylococcus aureus.
The proposed research project would be based around developing specific inhibitor drug combination therapies for treatment of methicillin resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (CNS). Multi-drug resistant strains of these pathogens are among the most clinically significant examples of microbial resistance to aminoglycoside antibiotics (Davies and Wright, 1997; Wright et al., 1998). Aminoglycoside antibiotics include kanamycin, tobramycin and the widely used clinical antibiotic gentamicin of which particular strains have shown resistance (Doebbeling, 1995). This goal would be achieved by structure-based studies of the aminoglycoside modifying enzyme AAC[6']-Im. This enzyme is of particular interest due to its similarities in sequence and substrate profile to the autonomously functioning N-terminal domain of the bifunctional aminoglycoside-modifying enzyme AAC(6')-APH(2''). This enzyme has been shown to confer high-level resistance to the aminoglycoside antibiotics gentamicin, tobramycin and kanamycin and has phospo- and acetyl- transferase modes of aminoglycoside modification (Daigle et al., 1999; Boehr et al., 2003). Indeed the aacA-aphD gene coding for this enzyme appears to be singularly responsible for gentamicin resistance in staphylococci and the most effective mediator of high-level resistance in major Gram-positive pathogens to virtually all aminoglycoside antibiotics (Culebras and Martinez, 1999). However, no reported studies have been carried out on the development of inhibitors of the enzyme family represented by the acetyltransferase N-terminal domain of the bifuntional protein AAC[6']-Ie-APH(2'')-Ia.
Protein Crystallography and Protein Chemistry
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The opportunity ID for this research opportunity is: 29