Degradation of Mecillinam in Aqueous Solution

Baltzer, B.; Lund, Frederick H.; Rastrup-Andersen, Niels

doi:10.1002/jps.2600681005

Cited by 27 publications

(23 citation statements)

References 29 publications

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“…A peak at 1278 cm −1 , 149 which is believed to arise from the amidine link in the mecillinam molecule (see Fig 1 150 and Methods), clearly disappears over time. This is consistent with evidence that the 151 primary degradation pathway for mecillinam is via hydrolysis of the amidine bond [16]. 152 Fitting an exponential decay function to the peak height (relative to the background 153 spectrum) at 1278 cm −1 as a function of time gives a half-life of 1.3 ± 0.4 hours 154 ( Fig 4D), consistent with our result from the delay time bioassay.…”

supporting

confidence: 85%

“…Antibiotic degradation in aqueous solution has been extensively studied in the 10 chemical literature [15][16][17][18][19], and it is well-known that, under some conditions, 11 antibiotics can degrade on timescales much shorter than a typical bacterial growth assay. 12 There has been little work, however, on how quickly antibiotics degrade in standard 13 laboratory growth media, such as those used for MIC assays.…”

mentioning

confidence: 99%

“…Mecillinam is somewhat peculiar among β-lactams since its side chain is 55 linked to the core part of the penicillin molecule (the 6-aminopenicillanic acid moiety) 56 via an amidine bond rather than the more usual amide bond ( Fig 1A). Its degradation 57 has been shown to be highly pH-sensitive in aqueous solution, with a maximum half-life 58 at pH 5 (at 37 • C) of around 200 hours [16]. Aztreonam ( Fig 1B) is a synthetic degradation of cefotaxime has been found to be strongly affected by solvolytic, hydrogen 71 ion and hydroxide ion catalysis, with maximum stability at pH 4.5 -6.5 (at 25 • C) in 72 aqueous solution [36].…”

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Stability ofβ-lactam antibiotics in bacterial growth media

Brouwers

Vass

Dawson

et al. 2020

Preprint

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Laboratory assays such as MIC tests assume that antibiotic molecules are stable in the chosen growth medium -but rapid degradation has been observed for antibiotics including β-lactams under some conditions in aqueous solution. Degradation rates in bacterial growth medium are less well known. Here, we develop a 'delay time bioassay' that provides a simple way to estimate antibiotic stability in bacterial growth media. We use the bioassay to measure degradation half-lives of the β-lactam antibiotics mecillinam, aztreonam and cefotaxime in widely-used bacterial growth media based on MOPS and Luria-Bertani (LB) broth. We find that mecillinam degradation can occur rapidly, with a half-life as short as 2 hours in MOPS medium at 37 • C and pH 7.4, and 4-5 hours in LB, but that adjusting the pH and temperature can increase its stability to a half-life around 6 hours without excessively perturbing growth. Aztreonam and cefotaxime were found to have half-lives longer than 6 hours in MOPS medium at 37 • C and pH 7.4, but still shorter than the timescale of a typical minimum inhibitory concentration (MIC) assay. Taken together, our results suggest that care is needed in interpreting MIC tests and other laboratory growth assays for β-lactam antibiotics, since there may be significant degradation of the antibiotic during the assay.Antibiotic efficacy is usually quantified by the minimal inhibitory concentration (MIC), 2 or the concentration of antibiotic needed to prevent bacterial growth over 24 hours in a 3 standard laboratory growth medium [1]; the MIC value plays a central role in 4 diagnostic and therapeutic decision-making. When performing an MIC assay, one 5 assumes that the antibiotic does not degrade over the timescale of the assay. Antibiotic 6 stability is also assumed in a host of other bacterial growth assays that are used to 7 determine antibiotic mechanism of action [2][3][4][5], interactions between antibiotics [6-9], 8 and evolution of antibiotic resistance [10][11][12][13][14]. 9Antibiotic degradation in aqueous solution has been extensively studied in the 10 chemical literature [15][16][17][18][19], and it is well-known that, under some conditions, 11 antibiotics can degrade on timescales much shorter than a typical bacterial growth assay. 12 There has been little work, however, on how quickly antibiotics degrade in standard 13 laboratory growth media, such as those used for MIC assays. Here, we develop a 14 'delay-time bioassay', based on growth measurements in a plate reader, that allows 15 simple estimation of the rate of antibiotic degradation in bacterial growth media. 16Bacterial growth media are chemically complex, since bacterial proliferation requires 17 carbon, nitrogen, phosphorous, iron and a diverse array of micronutrients [20,21]. 18April 14, 2020 1/18 "Undefined" growth media contain ingredients such as yeast extract, blood or beef 19 extract, whose detailed chemical composition is not known. Luria-Bertani (LB) medium, 20 which consists of water, tryptone, sodium chloride and yeast extract, i...

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confidence: 85%

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confidence: 99%

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Stability ofβ-lactam antibiotics in bacterial growth media

Brouwers

Vass

Dawson

et al. 2020

Preprint

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“…The tritiation was performed by treating dehydro-mecillinam 9 and 10% Pd/C in water with tritium-gas at 218C/1 atm for 2 h. Both the imino-functionality and the b-lactam ring were stable under those conditions. 11 Purification by reversed phase HPLC (cf. Strojny and Silva 12 ) afforded the desired product 10b with 96% radiochemical purity and a specific activity of 24 Ci/mmol.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of tritium labelled mecillinam

Frederiksen

Grue-Sørensen

2003

Labelled Comp Radiopharmac

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SummaryThe potent b-lactam antibiotic mecillinam has successfully been labelled with tritium. 2,3,4,7-Tetrahydro-1H-azepin-1-carbaldehyde was formed in a ring-closing metathesis reaction and then condensed with trimethylsilyl protected penicillanic acid to give dehydro-mecillinam. Pd/C catalysed tritiation then gave [ 3 H 2 ]-mecillinam (6-b (([3,4-3 H 2 ]hexahydro-1H-azepin-1-yl)methyleneamino)penicillanic acid) with a radiochemical purity of 96% and a specific activity of 24 Ci/mmol.

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“…Par- Table 10. Structure-activity relationships of 6-/l-amidinopenicillin analogs (BALTZER et al 1979), it is not appreciably absorbed by the oral route (ROHOLT et al 1975). The pivaloyloxymethyl ester (Table 1) is well absorbed orally and is hydrolyzed in the process to give clinically effective levels of the parent antibiotic (GAMBERTOGLIO et al 1980).…”

Section: Acylampicillinsmentioning

confidence: 99%

β-Lactam Antibiotics: Structure-Activity Relationships

Hoover¹

1983

Antibiotics

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Degradation of Mecillinam in Aqueous Solution

Cited by 27 publications

References 29 publications

Stability ofβ-lactam antibiotics in bacterial growth media

Stability ofβ-lactam antibiotics in bacterial growth media

Synthesis of tritium labelled mecillinam

β-Lactam Antibiotics: Structure-Activity Relationships

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