Comparing aminoglycoside binding sites in bacterial ribosomal RNA and aminoglycoside modifying enzymes

Abstract

Aminoglycoside antibiotics are used against severe bacterial infections. They bind to the bacterial ribosomal RNA and interfere with the translation process. However, bacteria produce aminoglycoside modifying enzymes (AME) to resist aminoglycoside actions. AMEs form a variable group and yet they specifically recognize and efficiently bind aminoglycosides, which are also diverse in terms of total net charge and the number of pseudo-sugar rings. Here, we present the results of 25 molecular dynamics simulations of three AME representatives and aminoglycoside ribosomal RNA binding site, unliganded and complexed with an aminoglycoside, kanamycin A. A comparison of the aminoglycoside binding sites in these different receptors revealed that the enzymes efficiently mimic the nucleic acid environment of the ribosomal RNA binding cleft. Although internal dynamics of AMEs and their interaction patterns with aminoglycosides differ, the energetical analysis showed that the most favorable sites are virtually the same in the enzymes and RNA. The most copied interactions were of electrostatic nature, but stacking was also replicated in one AME:kanamycin complex. In addition, we found that some water-mediated interactions were very stable in the simulations of the complexes. We show that our simulations reproduce well findings from NMR or X-ray structural studies, as well as results from directed mutagenesis. The outcomes of our analyses provide new insight into aminoglycoside resistance mechanism that is related to the enzymatic modification of these drugs.

Inhibitors of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] identified by in silico molecular docking

“…In this predicted model a short distance between an amino acid and the inhibitor is an indicator of interaction strength. As it can be seen in Figure 2, amino acids D115 and D152 are near the inhibitor molecule, which agrees with results obtained by X-ray crystallography of AAC(6′)-Ib complexed to kanamycin C and acetyl CoA 21 and by molecular dynamics simulations 29 .…”

Ligand promiscuity through the eyes of the aminoglycoside N3 acetyltransferase IIa

“…A coordinated dynamics may be more important instead, which may separate these two enzymes. Consistent with these data, a recent computational work also suggested that dynamics of each AGME and their interactions with the same AG may be different …”

Structure of AadA fromSalmonella enterica: a monomeric aminoglycoside (3′′)(9) adenyltransferase

“…4c; see below). The negative charge may mimic the nucleic acid environment that the aminoglycosides bind to in the ribosome (Romanowska et al, 2013) and is required for binding of the positively charged drug molecules.…”