Synthesis of 6-unsubstituted olivanic acid analogues and their antibacterial activities.

Basker, Michael J.; Bateson, John H.; Baxter, Andrew; Ponsford, Roger J.; Roberts, Patricia; Southgate, Robert; Smale, T. C.; Mith, Jennifers

doi:10.7164/antibiotics.34.1224

Cited by 13 publications

(6 citation statements)

References 10 publications

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“…As mentioned above, several chemical approaches were developed for the synthesis of carbapenems since fermentation was not an efficient method for production (9,28,86,142,183,201). Natural products (L-Cys, L-Val, L-␣-amino adipic acid, and S-adenosyl-Met) were often used as starting material for production of carbapenems, and the synthetic approach was largely influenced by the desired stereochemistry of the final compound.…”

Section: In the Beginning…mentioning

confidence: 99%

Carbapenems: Past, Present, and Future

Papp-Wallace

Endimiani

Taracila

et al. 2011

Antimicrob Agents Chemother

1,089

891

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In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the ␤-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most ␤-lactamases, in some cases act as "slow substrates" or inhibitors of ␤-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting ␤-lactamases serves as a major rationale for expansion of this class of ␤-lactams. We describe the initial discovery and development of the carbapenem family of ␤-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.Carbapenems play a critically important role in our antibiotic armamentarium. Of the many hundreds of different ␤-lactams, carbapenems possess the broadest spectrum of activity and greatest potency against Gram-positive and Gram-negative bacteria. As a result, they are often used as "last-line agents" or "antibiotics of last resort" when patients with infections become gravely ill or are suspected of harboring resistant bacteria (23,(174)(175)(176)229). Unfortunately, the recent emergence of multidrug-resistant (MDR) pathogens seriously threatens this class of lifesaving drugs (189). Several recent studies clearly show that resistance to carbapenems is increasing throughout the world (35,64,73,123,151,155,173,200). Despite this menacing trend, our understanding of how to best use these agents is undergoing a renaissance, especially concerning their role with regard to ␤-lactamase inhibition. In this context, we view the number, type, and diversity of carbapenems as compelling reasons to explore these compounds for new insights into drug development.

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Section: In the Beginning…mentioning

confidence: 99%

Carbapenems: Past, Present, and Future

Papp-Wallace

Endimiani

Taracila

et al. 2011

Antimicrob Agents Chemother

1,089

891

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“…Analogs (6-unsubstituted) have been synthesized with the side-chain double bond cis as well as trans. Both are reported to exhibit activity against a wide range of bacteria with the trans isomer slightly, but not significantly, more active than the cis isomer (BAXTER et al 1980;BASKER et al 1981). In fact, replacement of this side chain by hydrogen or phenyl results in derivatives with activities equivalent to the natural analogs with non basic (Nacetylated) side chains (Table 47).…”

Section: \0mentioning

confidence: 99%

β-Lactam Antibiotics: Structure-Activity Relationships

Hoover¹

1983

Antibiotics

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“…It has been proposed that this moiety restricts water access to the active site of the β-lactamase after acylation to hinder hydrolysis and regeneration of the active enzyme. 2, 3 Alternatively, it has been suggested that the hydroxyethyl forces a conformational change, placing the carbonyl of the covalent intermediate outside of the oxyanion hole, blocking hydrolysis. 4, 5 In keeping with either rationale, synthetic modification of clavulanic acid to attach a hydroxyethyl group at C-6 confers improved activity against Class C cephalosporinases.…”

Section: Introductionmentioning

confidence: 99%

“…These structural and kinetic insights have been exploited to engineer bLS to bind, adenylate, and cyclize a slightly larger substrate from stereospecific introduction of a short, neutral, alkyl chain on the substrate CEA (5). It is known that similarly placed side chains in carbapenem substrates can be regio-and stereospecifically hydroxylated enzymatically to give the (8R)hydroxyl group present, for example, in thienamycin (2). 17 To accommodate a larger substrate, the V446A and V446G mutants of bLS were selected to evaluate the diastereomeric preference of these variants for a (2 0 S)-or (2 0 R)-methyl group in N 2 -(2 0 -carboxypropyl)-L-arginine (2 0 -Me-CEA diastereomers, 10, Scheme 3) in the two-step b-lactam-forming reaction.…”

Section: Introductionmentioning

confidence: 99%

Engineering the synthetic potential of β-lactam synthetase and the importance of catalytic loop dynamics

et al. 2012

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The 2-azetidinone ring of the Class A and D β-lactamase inhibitor clavulanic acid (1) is synthesized by the ATP-utilizing enzyme β-lactam synthetase (βLS). A hydroxyethyl group attached to C-6 of 1 in the (S) configuration markedly enhances the efficacy of this compound against Class C β-lactamases. Guided by a series of X-ray structures of βLS, we have engineered this enzyme to act upon a methylated substrate analogue to give selectively the (3S)-methyl β-lactam core, which, upon closure of the second ring of the bicyclic system of 1, would lead to the (6S)-methylated clavulanic acid derivative.

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Synthesis of 6-unsubstituted olivanic acid analogues and their antibacterial activities.

Cited by 13 publications

References 10 publications

Carbapenems: Past, Present, and Future

Carbapenems: Past, Present, and Future

β-Lactam Antibiotics: Structure-Activity Relationships

Engineering the synthetic potential of β-lactam synthetase and the importance of catalytic loop dynamics

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