<i>In Vitro</i>
            Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

Page, Malcolm G. P.; Dantier, Clothilde; Desarbre, Eric

doi:10.1128/aac.01525-09

Cited by 204 publications

(179 citation statements)

References 49 publications

(55 reference statements)

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“…We (31) and others (15) previously identified the TBDRs PiuA and PirA as important to the activity of the siderophore-drug conjugates BAL30072 and MC-1 in P. aeruginosa. Since BAL30072 also shows potent activity toward A. baumannii (14,18,32), we attempted to identify its mechanism of action in the organism. We performed a homology search for potential orthologues of PiuA and PirA on the genome of A. baumannii reference strain ATCC 19606 (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…The iron-binding moiety of beta-lactam siderophore conjugates is frequently a small catechol-type siderophore, such as dihydroxypyridone or a mixed catechol-hydroxamate (7). Such conjugates have been developed with aminopenicillins (8), cephems (KP-736 and S-649266) (9)(10)(11), and monocyclic beta-lactams (pirazmonam, BAL30072, and MC-1) (12)(13)(14)(15). In particular, the monobactam conjugates show potent activity against the Gram-negative nonfermenters P. aeruginosa and A. baumannii (15)(16)(17)(18).…”

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confidence: 99%

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Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

Moynié

Lüscher

Rolo

et al. 2017

Antimicrob Agents Chemother

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106

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The outer membrane of Gram-negative bacteria presents an efficient barrier to the permeation of antimicrobial molecules. One strategy pursued to circumvent this obstacle is to hijack transport systems for essential nutrients, such as iron. BAL30072 and MC-1 are two monobactams conjugated to a dihydroxypyridone siderophore that are active against Pseudomonas aeruginosa and Acinetobacter baumannii. Here, we investigated the mechanism of action of these molecules in A. baumannii. We identified two novel TonB-dependent receptors, termed Ab-PiuA and Ab-PirA, that are required for the antimicrobial activity of both agents. Deletion of either piuA or pirA in A. baumannii resulted in 4-to 8-fold-decreased susceptibility, while their overexpression in the heterologous host P. aeruginosa increased susceptibility to the two siderophore-drug conjugates by 4-to 32-fold. The crystal structures of PiuA and PirA from A. baumannii and their orthologues from P. aeruginosa were determined. The structures revealed similar architectures; however, structural differences between PirA and PiuA point to potential differences between their cognate siderophore ligands. Spontaneous mutants, selected upon exposure to BAL30072, harbored frameshift mutations in either the ExbD3 or the TonB3 protein of A. baumannii, forming the cytoplasmic-membrane complex providing the energy for the siderophore translocation process. The results of this study provide insight for the rational design of novel siderophore-drug conjugates against problematic Gramnegative pathogens.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

Moynié

Lüscher

Rolo

et al. 2017

Antimicrob Agents Chemother

Self Cite

106

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“…The siderophore‐containing β‐lactam BAL30072 ( 47 ; Figure 33, developed by Basilea Pharmaceutica AG)155 is a siderophore sulfactam conjugate derived from tigemonam ( 48 ) with an additional dihydroxypyridinone moiety to chelate iron 156. It serves as a bioisostere for catechol, and the BAL30072‐Fe 3+ complex can thus be actively transported through the outer membrane 157.…”

Section: Cell Wall Synthesis Inhibitorsmentioning

confidence: 99%

“…Inside the bacteria, it inhibits PBP1a, PBP2a, and PBP3 and acts as an inhibitor of class C β‐lactamases 155. BAL30072 shows good antibacterial activity in vitro against Gram‐negative bacteria, is active in vivo against Acinetobacter baumannii , and features synergistic activity in combination with carbapenems 155, 158, 159…”

Section: Cell Wall Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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“…Synthesis of vinyl and ethyl substituted cores began with Boc-D-serine methyl ester (15). Silylation of the primary alcohol with TBSCl followed by DIBAL-H reduction of the ester and vinyl Grignard addition to the resultant aldehyde produced alcohol 16 as a ∼1:1 mixture of diastereomers.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

SAR and Structural Analysis of Siderophore-Conjugated Monocarbam Inhibitors of Pseudomonas aeruginosa PBP3

Murphy-Benenato

Dangel

Davis

et al. 2015

ACS Med. Chem. Lett.

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A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-β-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design. KEYWORDS: Pseudomonas aeruginosa, β-lactam, penicillin binding protein, siderophore, monocarbam, structure-guided design O ne of the largest challenges in the discovery of new Gram-negative antibacterial agents is the identification of chemotypes that can penetrate the cell envelope. 1 The pathogens, such as Pseudomonas aeruginosa (P. aeruginosa), have evolved complex cell architectures including an outer membrane composed of charged lipopolysaccharides, a thin peptidogylcan layer, and an inner membrane made up of phospholipids. 2 Identifying molecules with the necessary features to enable permeation has been a challenge.β-Lactams are one chemotype that have been successful in the treatment of P. aeruginosa. 3 Since the discovery of penicillin, β-lactams have been used in the clinic and are still widely prescribed. One of the most effective classes of β-lactams for the treatment of P. aeruginosa infections are the carbapenems (e.g., meropenem, 1, Figure 1). 4 Their effectiveness stems from their ability to acylate their penicillin-binding protein (PBP) targets, aided by high permeability into P. aeruginosa through the outer membrane porins. 5 However, they are currently being challenged in the clinic by the increasing emergence of broadspectrum serine β-lactamases and metallo-β-lactamases which hydrolyze most β-lactams and render them ineffective. 6 There is one class of β-lactams that is stable to the metallo-β-lactamases: the monocyclic β-lactams represented by aztreonam (2). Aztreonam however has limited effectiveness against P. aeruginosa presumably due to its poor permeation of the outer membrane, β-lactamase susceptibility, and high propensity for efflux (P. aeruginosa MIC 90 ≥ 1024 μg/mL, n = 20 panel). 3,7 To address the poor activity of 2, we focused on improving permeation by introducing siderophore mimics to promote uptake. 8−10 Siderophores are small Fe-chelating molecules synthesized and secreted by bacteria to scavenge iron from the host. 9,11 The iron-complexed siderophores are then brought into the cell via the iron uptake machinery, enabling the bacteria to access the much needed nutrient. It has been shown that introduction of iron-chelating groups to a monocyclic β-lactam scaffold ca...

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In Vitro Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

Cited by 204 publications

References 49 publications

Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

Targeting Antibiotic Resistance

SAR and Structural Analysis of Siderophore-Conjugated Monocarbam Inhibitors of Pseudomonas aeruginosa PBP3

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