Figure 6. Proposed mechanism underlying the effect of cyslabdan on the activity of imipenem against MRSA.

In MRSA, the first Gly is extended from the l-Lys of the pentapeptide region of the murein monomer (MurNAc-GlcNAc-pentapeptide) by FemX. The introduction of the second and third Gly is catalyzed by FemA, and the fourth and fifth Gly are added by FemB, to form (Gly)₅-murein monomers. PBP and/or PBP2′ finally catalyze the cross-linking of the fifth Gly and fourth d-Ala of the pentapeptide region in the next murein monomer together with the concomitant release of the terminal d-Ala of the pentapeptide. Imipenem alone: β-lactam inhibited PBP, but insensitive PBP2′ was able to cross-link (Gly)₅-murein monomers. Therefore, MRSA can grow even in the presence of imipenem. Cyslabdan alone: the nonantibiotic compound cyslabdan inhibited FemA, causing the accumulation of Gly-murein monomers, but PBP and/or PBP2′ were able to cross-link them; hence, MRSA can grow even in the presence of cyslabdan. Combination of imipenem and cyslabdan: MRSA was not able to grow, indicating that PBP2′ cannot cross-link Gly-murein monomers. In this illustration, the red cross indicates the observation that PBP2′ was not able to cross-link the resulting monoglycyl murein monomer to the next murein monomer.