Structure-activity relationships of some arylglycine analogues and catechol isosteres of BRL 36650, a 6.ALPHA.-formamido penicillin.

Best, Desmond J.; Burton, George; Davies, David T.; Elder, John S.; Smale, T. C.; Southgate, Robert; Stachulski, Andrew V.; Basker, Michael J.; Knott, Sarah J.

doi:10.7164/antibiotics.43.574

Cited by 4 publications

(2 citation statements)

References 8 publications

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“…First, 200 ml of 10ϫ cation-adjusted MHB (Difco) was chelated with 20 g of Chelex 100 resin (Bio-Rad) for 6 h at room temperature with constant stirring, after which the entire mixture was transferred to dialysis tubing (12,000 to 14,000 molecular weight cutoff) and dialyzed against 1.8 liters of distilled water for 16 h at 4°C. After removal of the dialysis tubing, the dialysate was sterilized either by autoclaving or by filtration, and 3.6 ml of 1 M MgSO 4 and 360 l of 1 M CaCl 2 were added to supplement the chelated Mg 2ϩ and Ca 2ϩ . Western blot analysis.…”

Section: Methodsmentioning

confidence: 99%

“…P. aeruginosa, K. pneumoniae, and A. baumannii can become resistant to certain ␤-lactam-type antibiotics by downregulating their major outer membrane porins (OprD, OmpK, and CarO, respectively), which limits compound entry into the Gram-negative periplasmic space (11,20,35). To address this widespread resistance phenotype, researchers have designed and developed siderophore-conjugated antimicrobial compounds (4,14,32). The incorporation of the siderophore allows for the hijacking of the normal siderophore-mediated iron uptake mechanisms used by pathogens such as P. aeruginosa, thereby avoiding the dependence on outer membrane porin expression for effective entry into cells.…”

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confidence: 99%

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Clinically Relevant Gram-Negative Resistance Mechanisms Have No Effect on the Efficacy of MC-1, a Novel Siderophore-Conjugated Monocarbam

McPherson

Aschenbrenner

Lacey

et al. 2012

Antimicrob Agents Chemother

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The incidence of hospital-acquired infections with multidrug-resistant (MDR) Gram-negative pathogens is increasing at an alarming rate. Equally alarming is the overall lack of efficacious therapeutic options for clinicians, which is due primarily to the acquisition and development of various antibiotic resistance mechanisms that render these drugs ineffective. Among these mechanisms is the reduced permeability of the outer membrane, which prevents many marketed antibiotics from traversing this barrier. To circumvent this, recent drug discovery efforts have focused on conjugating a siderophore moiety to a pharmacologically active compound that has been designed to hijack the bacterial siderophore transport system and trick cells into importing the active drug by recognizing it as a nutritionally beneficial compound. MC-1, a novel siderophore-conjugated ␤-lactam that promotes its own uptake into bacteria, has exquisite activity against many Gram-negative pathogens. While the inclusion of the siderophore was originally designed to facilitate outer membrane penetration into Gram-negative cells, here we show that this structural moiety also renders other clinically relevant antibiotic resistance mechanisms unable to affect MC-1 efficacy. Resistance frequency determinations and subsequent characterization of first-step resistant mutants identified PiuA, a TonB-dependent outer membrane siderophore receptor, as the primary means of MC-1 entry into Pseudomonas aeruginosa. While the MICs of these mutants were increased 32-fold relative to the parental strain in vitro, we show that this resistance phenotype is not relevant in vivo, as alternative siderophore-mediated uptake mechanisms compensated for the loss of PiuA under iron-limiting conditions.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Clinically Relevant Gram-Negative Resistance Mechanisms Have No Effect on the Efficacy of MC-1, a Novel Siderophore-Conjugated Monocarbam

McPherson

Aschenbrenner

Lacey

et al. 2012

Antimicrob Agents Chemother

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β‐Lactam Antibiotics

Testero

Fisher

Mobashery

2010

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam classes of antibacterials are preeminent in the treatment of bacterial infection due to their unparalleled clinical efficacy and clinical safety. Following the discovery of the penicillins, successive β‐lactam drug discovery has added the cephalosporin, penem cephamycin, clavulanate, monobactam, nocardicin, and carbapenem subclasses. The driving force behind much of this era of discovery is the staggering ability of pathogenic bacteria to adapt previous generations of the β‐lactam by the acquisition and expression of resistance mechanisms. Although many factors contribute to β‐lactam resistance, alterations to the molecular targets of the β‐lactams (the penicillin binding proteins) and the use of enzymes (the β‐lactamases) capable of the hydrolytic deactivation of the β‐lactams are paramount. This review traces the historical development of β‐lactam drug discovery, with emphasis on the most recent progress in the medicinal chemistry, biochemistry, and microbiology of the β‐lactams leading to the discovery of new generation β‐lactam antibacterials effective against the Gram‐negative and ‐positive bacterial pathogens of current medical concern.

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Chemistry and Synthesis of some Novel β -Lactam Antibiotics and β -Lactamase Inhibitors

Southgate¹,

Branch²,

Coulton³

et al. 1993

Recent Progress in the Chemical Synthesis of Antibiotics and Related Microbial Products Vol. 2

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Structure-activity relationships of some arylglycine analogues and catechol isosteres of BRL 36650, a 6.ALPHA.-formamido penicillin.

Cited by 4 publications

References 8 publications

Clinically Relevant Gram-Negative Resistance Mechanisms Have No Effect on the Efficacy of MC-1, a Novel Siderophore-Conjugated Monocarbam

Clinically Relevant Gram-Negative Resistance Mechanisms Have No Effect on the Efficacy of MC-1, a Novel Siderophore-Conjugated Monocarbam

β‐Lactam Antibiotics

Chemistry and Synthesis of some Novel β -Lactam Antibiotics and β -Lactamase Inhibitors

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