Interaction Between Acetohydroxamic Acid and 12 Antibiotics Against 14 Gram-Negative Pathogenic Bacteria

Abstract

Acetohydroxamic acid (AHA) is a potent inhibitor of urease which prevents alkalinization of urine and stone formation in rats in the presence of infection caused by urease-producing bacteria. Because an antibacterial effect of AHA, and synergy between kanamycin and AHA have also been described, we studied the interaction between AHA and 12 antibiotics against 14 gram-negative bacteria. Synergy, sometimes to a striking degree, was found in 17% of interactions; however, antagonism was detected in 5%. Infecting organisms would need to be studied individually before the antibacterial effect of AHA and an antibiotic could be predicted.Acetohydroxamic acid (AHA) has been shown to be an effective inhibitor of bacterial urease in vitro (1, 2, 5, 5b). Administration of AHA to rats greatly reduced the degree of stone formation in urinary infections caused by Proteus mirabilis (5a). These data suggest that AHA may be useful in treating chronic urinary tract infections that are accompanied by urolithiasis.Studies of antibacterial synergy have been prompted by two sets of observations: (i) AHA has bacteriostatic effects against many pathogenic gram-negative bacteria (5b); (ii) synergy between hydroxamic acids and kanamycin for several strains of Proteus has previously been described (5). In the present paper we present data on the interaction between AHA and 12 commonly used antibiotics against 14 pathogenic gram-negative bacteria.MATERIALS AND METHODS Organisms. Fourteen gram-negative pathogenic bacteria that had been isolated from patients with urinary tract infections were selected from the Diagnostic Microbiology Laboratory, V.A. Hospital, Houston. These included the following: five strains of Proteus (two of morganii and one each of mi-abilis, rettgeri, and vulgaris

Genetic analysis of an Escherichia coli urease locus: evidence of DNA rearrangement

“…Small-scale preparations of whole-cell DNA followed the protocol given below. A single colony from a fresh overnight growth on a urea-glucoseeosin Y-methylene blue agar plate was suspended in 500 ,ul of Tris hydrochloride at pH 8.0, 50 ,ul of 10-mg/ml lysozyme was added, and the sample was incubated at room temperature for 15 Cosmid cloning. Chromosomal DNA from E. coli 1021 was partially cleaved with the restriction endonuclease Sau3AI, sized on a sucrose gradient (10 to 40%), and ligated to the BamEII-digested and alkaline phosphatase-treated cosmid vector pREG153, a R388 derivative (8), as described elsewhere (10).…”

“…When produced by bacteria that infect the urinary tract, urease is thought to play a role in virulence. Alkaline urine results from an increased concentration of ammonium ions, which can lead to renal tissue damage (14), struvite stone formation (1,5,14,21,24,25), enhanced attachment of the infecting bacteria to bladder transitional epithelium (17), and inactivation of antibiotics (15). There is evidence that urease-producing bacteria have a predilection for the urinary tract (9,26).…”

Potentiation of the Antibacterial Effect of Methanamine by Acetohydroxamic Acid

“…(i) In contrast to the findings of others (2), we have previously shown that AHA has definite antibacterial effects (2b); these were demonstrated again in the present studies (Fig. 4 and 5). (ii) For reasons that remain obscure, but are unrelated to effects on pH, AHA may act synergistically or antagonistically with a variety of antibiotics against gram-negative urinary pathogens (4). In contrast, the potentiating effect of AHA for methenamine is directly related to its effect on pH (Fig.…”