Synthesis, Antibacterial Activity, and Nephrotoxicity of Polymyxin B Analogues Modified at Leu-7, <scp>d</scp>-Phe-6, and the N-Terminus Enabled by S-Lipidation

Harris, Paul W. R.; Siow, Andrew; Yang, Sung‐Hyun; Wadsworth, Andrew D.; Tan, Lyndia; Hermant, Yann; Mao, Yubing; An, Chalice; Hanna, Cameron C.; Cameron, Alan J.; Allison, Jane R.; Chakraborty, Aruna; Ferguson, Scott; Mros, Sonya; Hards, Kiel; Cook, Gregory M.; Williamson, Deborah A; Carter, Glen P.; Chan, Susanna T. S.; Painter, Gavin F.; Sander, Veronika; Davidson, Alan J.; Brimble, Margaret A.

doi:10.1021/acsinfecdis.1c00347

Cited by 12 publications

(13 citation statements)

References 71 publications

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“…As ATM/AVI combinations have been optimized for clinical trials, we have not investigated the PK properties of compounds 2c and 3 . Moreover, the potential nephrotoxicity of compounds 2c and 3 should be studied on primary kidney cells and compared to TOB and NEB controls. , …”

Section: Discussionmentioning

confidence: 99%

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Trimeric Tobramycin/Nebramine Synergizes β-Lactam Antibiotics against Pseudomonas aeruginosa

Dhiman,

Ramirez,

Arora

et al. 2023

ACS Omega

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β-Lactam antibiotics remain one of the most effective therapeutics to treat infections caused by Gram-negative bacteria (GNB). However, since ancient times, bacteria have developed multiple resistance mechanisms toward this class of antibiotics including overexpression of β-lactamases, suppression of porins, outer membrane impermeability, overexpression of efflux pumps, and target modifications. To cope with these challenges and to extend the lifetime of existing β-lactam antibiotics, βlactamase inhibitors are combined with β-lactam antibiotics to prevent antibiotic inactivation by β-lactamases. The combination therapy of an outer membrane permeabilizer with β-lactam antibiotics is an alternative approach to overcoming bacterial resistance of β-lactams in GNB. This approach is of particular interest for pathogens with highly impermeable outer membranes like Pseudomonas aeruginosa. Previous studies have shown that outer membrane permeabilizers can be designed by linking tobramycin and nebramine units together in the form of dimers or chimeras. In this study, we developed trimeric tobramycin and nebraminebased outer membrane permeabilizers presented on a central 1,3,5-triazine framework. The resultant trimers are capable of potentiating outer membrane-impermeable antibiotics but also β-lactams and β-lactam/β-lactamase inhibitor combinations against resistant P. aeruginosa isolates. Furthermore, the microbiological susceptibility breakpoints of ceftazidime, aztreonam, and imipenem were reached by a triple combination consisting of an outer-membrane permeabilizer/β-lactam/β-lactamase inhibitor in β-lactamresistant P. aeruginosa isolates. Overall, our results indicate that trimeric tobramycins/nebramines can rescue clinically approved βlactams and β-lactam/β-lactamase inhibitor combinations from resistance.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, the potential nephrotoxicity of compounds 2c and 3 should be studied on primary kidney cells and compared to TOB and NEB controls. 47,48 4. EXPERIMENTAL SECTION 4.1.…”

Section: Discussionmentioning

confidence: 99%

Trimeric Tobramycin/Nebramine Synergizes β-Lactam Antibiotics against Pseudomonas aeruginosa

Dhiman,

Ramirez,

Arora

et al. 2023

ACS Omega

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“…37 These organoids represent a valuable system for understanding the intricate communication between different kidney cell types impacted by nephrotoxic substances. 38 The control compound, commercially sourced polymyxin B, and synthetic 1 and 2 were tested by adding 100 μM, 300 μM, or 1 mM to the organoids at day 12 of the protocol, shown previously to correspond to the optimal maturity of the organoid tissues. Toxicity was determined after 48 h by scoring renal tubule deterioration using bright-field imaging (Figure 1).…”

Section: T H Imentioning

confidence: 99%

Synthesis, Structure–Activity Relationship Study, Bioactivity, and Nephrotoxicity Evaluation of the Proposed Structure of the Cyclic Lipodepsipeptide Brevicidine B

Palpal-latoc,

Horsfall,

Cameron

et al. 2024

J. Nat. Prod.

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The brevicidines represent a novel class of nonribosomal antimicrobial peptides that possess remarkable potency and selectivity toward highly problematic and resistant Gram-negative pathogenic bacteria. A recently discovered member of the brevicidine family, coined brevicidine B (2), comprises a single amino acid substitution (from d-Tyr2 to d-Phe2) in the amino acid sequence of the linear moiety of brevicidine (1) and was reported to exhibit broader antimicrobial activity against both Gram-negative (MIC = 2–4 μgmL–1) and Gram-positive (MIC = 2–8 μgmL–1) pathogens. Encouraged by this, we herein report the first total synthesis of the proposed structure of brevicidine B (2), building on our previously reported synthetic strategy to access brevicidine (1). In agreement with the original isolation paper, pleasingly, synthetic 2 demonstrated antimicrobial activity toward Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae (MIC = 4–8 μgmL–1). Interestingly, however, synthetic 2 was inactive toward all of the tested Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus strains. Substitution of d-Phe2 with its enantiomer, and other hydrophobic residues, yields analogues that were either inactive or only exhibited activity toward Gram-negative strains. The striking difference in the biological activity of our synthetic 2 compared to the reported natural compound warrants the re-evaluation of the original natural product for purity or possible differences in relative configuration. Finally, the evaluation of synthetic 1 and 2 in a human kidney organoid model of nephrotoxicity revealed substantial toxicity of both compounds, although 1 was less toxic than 2 and polymyxin B. These results indicate that modification to position 2 may afford a strategy to mitigate the nephrotoxicity of brevicidine.

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“…Another class of polymyxin analogues bearing modified N -terminal lipid moieties was recently reported by the group of Harris and Brimble wherein structural variation was introduced by employing thioether linked modifications . In these analogues, a number of S -alkylated Cys-derived building blocks were coupled to the N -terminus of the polymyxin decapeptide (Figure ).…”

Section: Polymyxin Analogues With Sar and (Nephro)toxicity Datamentioning

confidence: 99%

Recent Advances in the Development of Polymyxin Antibiotics: 2010–2023

Slingerland,

Martin

2024

ACS Infect. Dis.

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The polymyxins are nonribosomal lipopeptides produced by Paenibacillus polymyxa and are potent antibiotics with activity specifically directed against Gram-negative bacteria. While the clinical use of polymyxins has historically been limited due to their toxicity, their use is on the rise given the lack of alternative treatment options for infections due to multidrug resistant Gram-negative pathogens. The Gram-negative specificity of the polymyxins is due to their ability to target lipid A, the membrane embedded LPS anchor that decorates the cell surface of Gram-negative bacteria. Notably, the mechanisms responsible for polymyxin toxicity, and in particular their nephrotoxicity, are only partially understood with most insights coming from studies carried out in the past decade. In parallel, many synthetic and semisynthetic polymyxin analogues have been developed in recent years in an attempt to mitigate the nephrotoxicity of the natural products. Despite these efforts, to date, no polymyxin analogues have gained clinical approval. This may soon change, however, as at the moment there are three novel polymyxin analogues in clinical trials. In this context, this review provides an update of the most recent insights with regard to the structure−activity relationships and nephrotoxicity of new polymyxin variants reported since 2010. We also discuss advances in the synthetic methods used to generate new polymyxin analogues, both via total synthesis and semisynthesis.

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Synthesis, Antibacterial Activity, and Nephrotoxicity of Polymyxin B Analogues Modified at Leu-7, d-Phe-6, and the N-Terminus Enabled by S-Lipidation

Cited by 12 publications

References 71 publications

Trimeric Tobramycin/Nebramine Synergizes β-Lactam Antibiotics against Pseudomonas aeruginosa

Trimeric Tobramycin/Nebramine Synergizes β-Lactam Antibiotics against Pseudomonas aeruginosa

Synthesis, Structure–Activity Relationship Study, Bioactivity, and Nephrotoxicity Evaluation of the Proposed Structure of the Cyclic Lipodepsipeptide Brevicidine B

Recent Advances in the Development of Polymyxin Antibiotics: 2010–2023

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