posted on 2021-05-03, 17:33authored byAnderson H. Lima, José Rogério
A. Silva, Cláudio
Nahum Alves, Jerônimo Lameira
Multidrug-resistant
organisms contain antibiotic-modifying enzymes
that facilitate resistance to a variety of antimicrobial compounds.
Particularly, the fosfomycin (FOF) drug can be structurally modified
by several FOF-modifying enzymes before it reaches the biological
target. Among them, FosB is an enzyme that utilizes l-cysteine
or bacillithiol in the presence of a divalent metal to open the epoxide
ring of FOF and, consequently, inactivate the drug. Here, we have
used hybrid quantum mechanics/molecular mechanics (QM/MM) and molecular
dynamics (MD) simulations to explore the mechanism of the reaction
involving FosB and FOF. The calculated free-energy profiles show that
the cost to open the epoxide ring of FOF at the C2 atom is ∼3.0
kcal/mol higher than that at the C1 atom. Besides, our QM/MM MD results
revealed the critical role of conformation change of Cys9 and Asn50
to release the drug from the active site. Overall, the present study
provides insights into the mechanism of FOF-resistant proteins.