Solution structure of linear battacin lipopeptides – the effect of lengthening fatty acid chain

Kihara, Shinji; Zoysa, Gayan Heruka De; Shahlori, Rayomand; Vadakkedath, Praveen G.; Ryan, Timothy M.; Mata, Jitendra; Sarojini, Vijayalekshmi; McGillivray, Duncan J.

doi:10.1039/c9sm00932a

Cited by 3 publications

(2 citation statements)

References 47 publications

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“…Furthermore, SAR studies enabled via Ala scanning allowed for optimization of the lipidated linear analogue sequence. Indeed, Kihara et al confirmed the significance of the N-terminal lipid, demonstrating the tendency for different lipidated battacin analogues to form various aggregation shapes depending on the lipid present, which correlated to differences in antibacterial activity . Inspired by this work, the Brimble group sought to further probe the SAR of battacin through generation of a library of linear analogues bearing various lipids installed using CLipPA S -lipidation (Scheme ).…”

Section: Antibiotics Against Gram-negative Bacterial Infectionsmentioning

confidence: 94%

Discovery, Synthesis, and Optimization of Peptide-Based Antibiotics

et al. 2021

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Conspectus The rise of multidrug resistant bacteria has significantly compromised our supply of antibiotics and poses an alarming medical and economic threat to society. To combat this problem, it is imperative that new antibiotics and treatment modalities be developed, especially those toward which bacteria are less capable of developing resistance. Peptide natural products stand as promising candidates to meet this need as bacterial resistance is typically slow in response to their unique modes of action. They also have additional benefits including favorable modulation of host immune responses and often possess broad-spectrum activity against notoriously treatment resistant bacterial biofilms. Moreover, nature has provided a wealth of peptide-based natural products from a range of sources, including bacteria and fungi, which can be hijacked in order to combat more dangerous clinically relevant infections. This Account highlights recent advances in the total synthesis and development of a range of peptide-based natural product antibiotics and details the medicinal chemistry approaches used to optimize their activity. In the context of antibiotics with potential to treat Gram-positive bacterial infections, this Account covers the synthesis and optimization of the natural products daptomycin, glycocin F, and alamethicin. In particular, the reported synthesis of daptomycin highlights the utility of on-resin ozonolysis for accessing a key kynurenine residue from the canonical amino acid tryptophan. Furthermore, the investigation into glycocin F analogues uncovered a potent lead compound against Lactobacillus plantarum that bears a non-native thioacetal linkage to a N-acetyl-d-glucosamine (GlcNAc) sugar, which is otherwise O-linked in its native form. For mycobacterial infections, this Account covers the synthesis and optimization of teixobactin, callyaerin A, lassomycin, and trichoderin A. The synthesis of callyaerin A, in particular, highlighted the importance of a (Z)-2,3-diaminoacrylamide motif for antimicrobial activity against Mycobacterium tuberculosis, while the synthesis of trichoderin A highlighted the importance of (R)-stereoconfiguration in a key 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) residue. Lastly, this Account covers lipopeptide antibiotics bearing activity toward Gram-negative bacterial infections, namely, battacin and paenipeptin C. In both cases, optimization of the N-terminal lipid tails led to the identification of analogues with potent activity toward Escherichia coli and Pseudomonas aeruginosa.

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Section: Antibiotics Against Gram-negative Bacterial Infectionsmentioning

confidence: 94%

Discovery, Synthesis, and Optimization of Peptide-Based Antibiotics

et al. 2021

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“…To overcome the toxicity of naturally occurring battacin, we previously designed and synthesized novel structural analogs . Remarkably and in contrast to other AMPs, such as polymyxin, two of these linear peptides, octapeptide 17 (hereafter octapeptide) and its derivative pentapeptide 30 (hereafter pentapeptide) (Figure ), were found experimentally to be active, in terms of both lysing bacteria and dispersing preformed biofilms, against both model Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria. , Unlike many AMPs, ,, the activity of these battacin analogs does not rely on the presence of a defined secondary structure when bound to the membrane, , suggesting that the mechanism of action might also differ. It is extremely difficult to experimentally obtain a detailed atomic level insight into their mechanism of action, however.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation of the Interaction of Two Linear Battacin Analogs with Model Gram-Positive and Gram-Negative Bacterial Cell Membranes

et al. 2020

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Antimicrobial peptides (AMPs) are a potential solution to the increasing threat of antibiotic resistance, but successful design of active but nontoxic AMPs requires understanding their mechanism of action. Molecular dynamics (MD) simulations can provide atomic-level information regarding how AMPs interact with the cell membrane. Here, we have used MD simulations to study two linear analogs of battacin, a naturally occurring cyclic, lipidated, nonribosomal AMP. Like battacin, these analogs are active against Gram-negative multidrug resistant and Gram-positive bacteria, but they are less toxic than battacin. Our simulations show that this activity depends upon a combination of positively charged and hydrophobic moieties. Favorable interactions with negatively charged membrane lipid head groups drive association with the membrane and insertion of hydrophobic residues, and the Nterminal lipid anchors the peptides to the membrane surface. Both effects are required for stable membrane binding.

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Interactions of Linear Analogues of Battacin with Negatively Charged Lipid Membranes

et al. 2021

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The increasing resistance of bacteria to available antibiotics has stimulated the search for new antimicrobial compounds with less specific mechanisms of action. These include the ability to disrupt the structure of the cell membrane, which in turn leads to its damage. In this context, amphiphilic lipopeptides belong to the class of the compounds which may fulfill this requirement. In this paper, we describe two linear analogues of battacin with modified acyl chains to tune the balance between the hydrophilic and hydrophobic portion of lipopeptides. We demonstrate that both compounds display antimicrobial activity with the lowest values of minimum inhibitory concentrations found for Gram-positive pathogens. Therefore, their mechanism of action was evaluated on a molecular level using model lipid films mimicking the membrane of Gram-positive bacteria. The surface pressure measurements revealed that both lipopeptides show ability to bind and incorporate into the lipid monolayers, resulting in decreased ordering of lipids and membrane fluidization. Atomic force microscopy (AFM) imaging demonstrated that the exposure of the model bilayers to lipopeptides leads to a transition from the ordered gel phase to disordered liquid crystalline phase. This observation was confirmed by attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) results, which revealed that lipopeptide action causes a substantial increase in the average tilt angle of lipid acyl chains with respect to the surface normal to compensate for lipopeptide insertion into the membrane. Moreover, the peptide moieties in both molecules do not adopt any well-defined secondary structure upon binding with the lipid membrane. It was also observed that a small difference in the structure of a lipophilic chain, altering the balance between hydrophobic and hydrophilic portion of the molecules, results in different insertion depth of the active compounds.

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Solution structure of linear battacin lipopeptides – the effect of lengthening fatty acid chain

Abstract: Explaining antimicrobial battacin lipopeptides by investigating the solution structure – the propensity to aggregate may have a role in a declined antimicrobial activity.

Cited by 3 publications

References 47 publications

Discovery, Synthesis, and Optimization of Peptide-Based Antibiotics

Discovery, Synthesis, and Optimization of Peptide-Based Antibiotics

Molecular Dynamics Simulation of the Interaction of Two Linear Battacin Analogs with Model Gram-Positive and Gram-Negative Bacterial Cell Membranes

Interactions of Linear Analogues of Battacin with Negatively Charged Lipid Membranes

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