Abstract
Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.
Highlights
Antimicrobial resistance is a major global threat that calls for new antibiotics
While lspA is essential in Gram-negative bacteria such as E. coli and P. aeruginosa, the lspA gene is not essential in Gram-positive monoderm bacteria including S. aureus[6,9]
LspAdeficient mutants of a methicillin-sensitive S. aureus (MSSA) strain were shown to be attenuated in a mouse model of infection and a signature-tagged mutagenesis screen in an MSSA background showed that disruption of lspA led to a loss of virulence in a mouse model of bacteremia[10,11]
Summary
Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillinresistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. One approach to species-specific drug development is through structure-based drug design This requires the structure of at least one of the target orthologs, ideally at high resolution. Having the structure of orthologs from other pathogenic species would prove extremely valuable This is the goal of the current study, focussed on the lipoprotein signal peptidase II, LspA (abbreviations are included in Supplementary Table 1), an enzyme involved in lipoprotein posttranslational processing in bacteria (Fig. 1). Whilst globomycin approaches from one side of the substrate-binding pocket, myxovirescin does so from the other Where these chemically and structurally distinct antibiotics overlap in the complex provides a blueprint for a drug development program. In combination with the high-resolution structure of LspA from P. aeruginosa (LspPae), these two structures set the stage for a campaign aimed at species-specific as well as broad-spectrum drug discovery
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