Synercid will do very well. It is an indirect but effective competitor to MCDE's first effort, the PBP2a inhibitor that is in development with Ortho. For those that follow this story, Synercid has been expected for some time. It should be a blockbuster some day. In contrast, I don't know of anyone that expects the first beta lactam from MCDE to achieve blockbuster status. Here's an abstract that I find useful, talking about the potential routes that a bug has for evading the MCDE approach. It also discusses some of the background rationale for the second Ortho project, the methicillin potentiator that is designed to stop the expression of PBP2a rather than to inhibit it once synthesized.
Rick
APMIS 1997 Apr;105(4):264-276
Mechanisms of methicillin resistance in staphylococci.
Brakstad OG, Maeland JA
SINTEF Applied Chemistry, Trondheim, Norway.
The continuously high prevalence of methicillin-resistant staphylococci (MRS) throughout the
world is a constant threat to public health, owing to the multiresistant characteristics of these
bacteria. Methicillin resistance is phenotypically associated with the presence of the
penicillin-binding protein 2a (PBP2a) not present in susceptible staphylococci. This protein has
a low binding affinity for beta-lactam antibiotics. It is a transpeptidase which may take over cell
wall synthesis during antibiotic treatment when normally occurring PBPs are inactivated by
ligating beta-lactams. PBP2a is encoded by the mecA gene, which is located in mec, a foreign
DNA region. Expression of PBP2a is regulated by proteins encoded by the plasmid-borne
blaR1-bla1 inducer-repressor system and the corresponding genomic mecRl-mecl system. The
blaRl-blal products are important both for the regulation of beta-lactamase and for mecA
expression. Methicillin resistance is influenced by a number of additional factors, e.g. the
products of the chromosomal fem genes which are important in the synthesis of normal
peptidoglycan precursor molecules. Inactivation of fem-genes results in structurally deficient
precursors which are not accepted as cell wall building blocks by the ligating PBP2a
transpeptidase during antibiotic treatment. This may result in reduced resistance to beta-lactam
antibiotics. Inactivation of genes affecting autolysis has shown that autolytic enzymes are also of
importance in the expression of methicillin resistance. Methicillin resistance has evolved among
earth microorganisms for protection against exogenous or endogenous antibiotics. Presumably
the mec region was originally transferred from coagulase negative staphylococci (CNS) to
Staphylococcus aureus (SA). A single or a few events of this kind with little subsequent
interspecies transfer had been anticipated. However, recent data suggest a continuous
horizontal acquisition by S. aureus of mec, being unidirectional from CNS to SA. Methicillin
resistance may also be associated with mechanisms independent of mecA, resulting in
borderline methicillin resistance. These mechanisms include beta-lactamase hyperproduction,
production of methicillinases, acquisition of structurally modified normal PBPs, or the
appearance of small colony variants of SA. Most MRS are multiresistant, and the mec region
may harbour several resistance determinants, resulting in a clustering of resistance genes within
this region. |
