Synergistic antibacterial activity between L-norvalyl-L-1-aminoethylphosphonic acid and nocardicin A

Abstract

The phosphonopeptide L-norvalyl-L-1-aminoethylphosphonic acid [Nva-Ala(P)] has been studied in combination with 12 r-lactam antibiotics for activity against Pseudomonas aeruginosa. Nocardicin A was found to give the most potent synergistic combination with Nva-Ala(P). This interaction was widely observed in clinical isolates of P. aeruginosa in vitro and in a mouse septicemia model. Synergy was also observed in vitro and in vivo in several other species, including Proteus mirabilis, indole-positive Proteus spp., and Serratia marcescens. The interaction between Nva-Ala(P) and nocardicin A involved a strongly bacteriolytic mechanism. In addition, the individual components were complementary to one another in their action against organisms not showing synergy. These properties resulted in a broad spectrum of activity of the combination Nva-Ala(P) plus nocardicin A when used to treat experimental gram-negative bacterial infections.A synergistic antibacterial interaction between the phosphonopeptide alafosfalin (L-alanyl-L-1-aminoethylphosphonic acid) and other inhibitors of cell wall biosynthesis, such as ampicillin, cephalexin, mecillinam, and D-cycloserine, has been reported previously (1, 2). This property was also displayed by related phosphonopeptides derived from aminomethylphosphonic acid (5) Agents Chemother. 19th, Boston, Mass., abstr. no. 238, 1979). Of the latter, L-norvalyl-L-1-aminoethylphosphonic acid [Nva-Ala(P)] was of particular interest, as it possessed a broad antibacterial spectrum, including activity against Pseudomonas aeruginosa (3). We have studied combinations of Nva-Ala(P) with various 3-lactam antibiotics, including the monocyclic agent nocardicin A, with a view to improving its antipseudomonal activity. Nocardicin A is reported to have an unusually restricted spectrum of activity in vitro and in vivo but includes organisms such as P. aeruginosa, Proteus spp., and Serratia marcescens (14, 15) which are often refractory to treatment. In this paper, we have identified nocardicin A as an especially useful partner for Nva-Ala(P), giving synergy in several species, including P. aeruginosa, and a broad spectrum of activity against gram-negative bacterial infections in an animal model. MATERIALS AND METHODSCompounds. Nva-Ala(P) was synthesized by R. W. Lambert by the methods described previously (6). Samples of apalcillin (Sumitomo Chemical Co., Osaka, Japan), azlocillin

Use of the dehydrophos biosynthetic enzymes to prepare antimicrobial analogs of alaphosphin

“…8b), which when combined with nocardicin A has been shown to possess potent synergistic antibacterial activity. 38 In these assays, the conversion varied from 90% for norvaline and norleucine to less than 10% for alanine. We note that the overall efficiency of these reactions dependents on both the efficiency of the triple LeuRS mutant to recognize non-canonical amino acids and the ability of DhpH-C to recognize the mischarged aminoacyl-tRNA Leu .…”

Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

“…Initial studies also assessed the low acute toxicity (LD > 2000 mg/kg on laboratory mice and rats), indicating the suitability of the compound for further development. The synergistic antibacterial activity between l ‐norvalyl‐ l ‐1‐aminoethylphosphonic acid and nocardicin A 61 was reported as well, resulting in MIC values on Gram‐negative bacteria that decreased one order of magnitude, albeit by means of a currently unknown mechanism of action . Starting from pioneering studies on nocardicin A 61 , several mutational studies have been performed on Nocardia species in order to identify related metabolite compounds and their relevant biosynthetic nocX genes (X = E, D, B, A, F, G, H, I, K, L, J, R, N) .…”

“…The synergistic antibacterial activity between L-norvalyl-L-1-aminoethylphosphonic acid and nocardicin A 61 was reported as well, resulting in MIC values on Gram-negative bacteria that decreased one order of magnitude, albeit by means of a currently unknown mechanism of action. 125 Starting from pioneering studies on nocardicin A 61, several mutational studies have been performed on Nocardia species in order to identify related metabolite compounds and their relevant biosynthetic nocX genes (X = E, D, B, A, F, G, H, I, K, L, J, R, N). 126,129 NocJ gene was identified to encode for an epimerase responsible for the L-D interconversion of the isonocardicin-nocardicin homoseryl side chain.…”