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1. Lung SPLUNC1 Peptide Derivatives in the Lipid Membrane Headgroup Kill Gram-Negative Planktonic and Biofilm Bacteria

   Jakkampudi, Tanvi; Lin, Qiao; Mitra, Saheli; Qin, Weiheng; Kang, Ann; Chen, Jespar; Ryan, Emma; Wang, Runwuan; Gong, Yuqi; Heinrich, Frank; et al (May 2023, Biomacromolecules)

   Lu, Hua (Ed.)

   SPLUNC1 (short palate lung and nasal epithelial clone 1) is a multifunctional host defense protein found in human respiratory tract with antimicrobial properties. In this work we compare the biological activities of four SPLUNC1 antimicrobial peptide (AMP) derivatives using paired clinical isolates of the Gram-negative (G(-)) bacteria Klebsiella pneumoniae, obtained from eleven patients with/without colistin resistance. Secondary structural studies were carried out to study interactions between the AMPs and lipid model membranes (LMMs) utilizing circular dichroism (CD). Two peptides were further characterized using x-ray diffuse scattering (XDS) and neutron reflectivity (NR). A4-153 displayed superior antibacterial activity in both G(-) planktonic cultures and biofilms. NR and XDS revealed that A4-153 (highest activity) is located primarily in membrane headgroups, while A4-198 (lowest activity) is located in hydrophobic region. CD revealed that A4-153 is helical while A4-198 has little helical character, demonstrating that helicity and efficacy are correlated in these SPLUNC1 AMPs. 

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2. Arsinothricin, an arsenic-containing non-proteinogenic amino acid analog of glutamate, is a broad-spectrum antibiotic

   https://doi.org/10.1038/s42003-019-0365-y  

   Nadar, Venkadesh Sarkarai; Chen, Jian; Dheeman, Dharmendra S.; Galván, Adriana Emilce; Yoshinaga-Sakurai, Kunie; Kandavelu, Palani; Sankaran, Banumathi; Kuramata, Masato; Ishikawa, Satoru; Rosen, Barry P.; et al (April 2019, Communications Biology)

   Abstract The emergence and spread of antimicrobial resistance highlights the urgent need for new antibiotics. Organoarsenicals have been used as antimicrobials since Paul Ehrlich’s salvarsan. Recently a soil bacterium was shown to produce the organoarsenical arsinothricin. We demonstrate that arsinothricin, a non-proteinogenic analog of glutamate that inhibits glutamine synthetase, is an effective broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria, suggesting that bacteria have evolved the ability to utilize the pervasive environmental toxic metalloid arsenic to produce a potent antimicrobial. With every new antibiotic, resistance inevitably arises. ThearsN1gene, widely distributed in bacterial arsenic resistance (ars) operons, selectively confers resistance to arsinothricin by acetylation of the α-amino group. Crystal structures of ArsN1N-acetyltransferase, with or without arsinothricin, shed light on the mechanism of its substrate selectivity. These findings have the potential for development of a new class of organoarsenical antimicrobials and ArsN1 inhibitors. 

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3. Modification of narrow‐spectrum peptidomimetic polyurethanes with fatty acid chains confers broad‐spectrum antibacterial activity

   https://doi.org/10.1002/pi.5773  

   Peng, Chao; Zhang, Tian; Ortiz‐Ortiz, Deliris_N; Vishwakarma, Apoorva; Barton, Hazel_A; Joy, Abraham (February 2019, Polymer International)

   Abstract Each year, thousands of patients die from antimicrobial‐resistant bacterial infections that fail to respond to conventional antibiotic treatment. Antimicrobial polymers are a promising new method of combating antibiotic‐resistant bacterial infections. We have previously reported the synthesis of a series of narrow‐spectrum peptidomimetic antimicrobial polyurethanes that are effective against Gram‐negative bacteria, such asEscherichia coli; however, these polymers are not effective against Gram‐positive bacteria, such asStaphylococcus aureus. With the aim of understanding the correlation between chemical structure and antibacterial activity, we have subsequently developed three structural variants of these antimicrobial polyurethanes using post‐polymerization modification with decanoic acid and oleic acid. Our results show that such modifications converted the narrow‐spectrum antibacterial activity of these polymers into broad‐spectrum activity against Gram‐positive species such asS. aureus, however, also increasing their toxicity to mammalian cells. Mechanistic studies of bacterial membrane disruption illustrate the differences in antibacterial action between the various polymers. The results demonstrate the challenge of balancing antimicrobial activity and mammalian cell compatibility in the design of antimicrobial polymer compositions. © 2019 Society of Chemical Industry 

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4. Novel Helical Trp‐ and Arg‐Rich Antimicrobial Peptides Locate Near Membrane Surfaces and Rigidify Lipid Model Membranes

   https://doi.org/10.1002/anbr.202300013  

   Mitra, Saheli; Coopershlyak, Mark; Li, Yunshu; Chandersekhar, Bhairavi; Koenig, Rachel; Chen, Mei-Tung; Evans, Brandt; Heinrich, Frank; Deslouches, Berthony; Tristram-Nagle, Stephanie (April 2023, Advanced NanoBiomed Research)

   Antibiotics are losing effectiveness as bacteria become resistant to conventional drugs. To find new alternatives, antimicrobial peptides (AMPs) are rationally designed with different lengths, charges, hydrophobicities (H), and hydrophobic moments (μH), containing only three types of amino acids: arginine, tryptophan, and valine. Six AMPs with low minimum inhibitory concentrations (MICs) and <25% toxicity to mammalian cells are selected for biophysical studies. Their secondary structures are determined using circular dichroism (CD), which finds that the % α‐helicity of AMPs depends on composition of the lipid model membranes (LMMs): gram‐negative (G(−)) inner membrane (IM) >gram‐positive (G(+))> Euk33 (eukaryotic with 33 mol% cholesterol). The two most effective peptides, E2‐35 (16 amino acid [AA] residues) and E2‐05 (22 AAs), are predominantly helical in G(–) IM and G(+) LMMs. AMP/membrane interactions such as membrane elasticity, chain order parameter, and location of the peptides in the membrane are investigated by low‐angle and wide‐angle X‐ray diffuse scattering (XDS). It is found that headgroup location correlates with efficacy and toxicity. The membrane bending modulusK_Cdisplays nonmonotonic changes due to increasing concentrations of E2‐35 and E2‐05 in G(–) and G(+) LMMs, suggesting a bacterial killing mechanism where domain formation causes ion and water leakage. 

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5. Novel non-helical antimicrobial peptides insert into and fuse lipid model membranes

   https://doi.org/10.1039/D4SM00220B  

   Mitra, Saheli; Chandersekhar, Bhairavi; Li, Yunshu; Coopershlyak, Mark; Mahoney, Margot E; Evans, Brandt; Koenig, Rachel; Hall, Stephen_C L; Klösgen, Beate; Heinrich, Frank; et al (May 2024, Soft Matter)

   Cerbino, Roberto (Ed.)

   This research addresses the growing menace of antibiotic resistance by exploring antimicrobial peptides (AMPs) as alternatives to conventional antibiotics. 

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