Paromomycin interaction with aminoglycosides

Recently, Tor and co-workers have analysed the interaction between the cyclic analog 2 and the corresponding paromomycin derivative with the A-site sequence and also with the HIV TAR RNA fragment [47]. At pH 7.5, the decrease in affinity for the locked derivatives with respect to the parent aminoglycosides is 22-14 fold for the A-site and 11-2 fold for the HIV TAR sequence. The differences with respect to the natural ligands are significantly reduced at acid pH. 

Figure 3.1A. Interaction of aminoglycosides with the acceptor site of the 30S ribosome. Schematic representation of (A) paromomycin and (B) streptomycin interactions with the 16S rRNA and ribosomal protein SI2.

The structures of tobramycin and neomycin B in complex with aptamer RNAs also display the importance of interactions between the amino groups of aminoglycosides and the phosphate backbone of RNA. In the neomycin-aptamer complex, the 6 -amino group on ring I interacts with the phosphate backbone. Paromomycin, in which the 6 position of ring I is a hydroxyl group, binds... 

Clinically important, potentially hazardous interactions with acitretin, aldesleukin, aminoglycosides, amiodarone, amoxicillin, ampicillin, aspirin, bacampicillin, bismuth, carbenicillin, chloroquine, cisplatin, cloxacillin, co-trimoxazole, dapsone, demeclocycline, dexamethasone, diclofenac, dicloxacillin, etodolac, etoricoxib, etretinate, fenoprofen, flurbiprofen, folic acid antagonists, haloperidol, hydrocortisone, ibuprofen, indomethacin, influenza vaccines, ketoprofen, ketorolac, lithium, magnesium trisalicylate, meclofenamate, mefenamic acid, methicillin, mezlocillin, minocycline, nabumetone, nafcillin, naproxen, NSAIDs, omeprazole, oxacillin, oxaprozin, oxytetracycline, paromomycin, penicillin G, penicillin V, penicillins, phenylbutazone, piperacillin, piroxicam, polypeptide antibiotics, prednisolone, prednisone, probenecid, procarbazine, rofecoxib, salicylates, salsalate, sapropterin, sulfadiazine, sulfamethoxazole, sulfapyridine, sulfasalazine, sulfisoxazole, sulindac, tazobactum, tenoxicam, tetracycline, ticarcillin, tolmetin, trimethoprim, vaccines... 

Clinically important, potentially hazardous interactions with amikacin, aminoglycosides, galantamine, gentamicin, kanamycin, neomycin, paromomycin, physostigmine, pipecuronium, streptomycin, tobramycin, vancomycin, vecuronium... 

Figure 6.4. Molecular interactions between 4,5 and 4,6 linked aminoglycosides and 308 (E. coli numbering, top) with various modifications tested for activity (bottom). Dashed lines indicate possible hydrogen bonds (some of which are salt bridges when suitably reinforced with favorable electrostatic potentials). Arrows point to permissible modifications arrows with an X point to non-permis-sible modifications, (a) Paromomycin ring I. The arrow with a points to a modification that was shown to be inactive, but is not readily explained by the crystal structure, (b) Paromomycin ring II. (c) Paromomycin ring III. (d) Paromomycin ring IV, (e) Gentamicin C1 a ring HI.

The documentation of these interactions is sparse, but it would seem prudent to be on the alert for a reduction in the response to methotrexate if patients are given oral aminoglycosides such as paromomycin or neomycin. An increased response may possibly occur with kanamycin. No interaction would be expected if aminoglycosides are given parenterally. 

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