“… Figure 6 Venn diagram showing the number of unique and shared targets identified using the three different ranking strategies for drug targeting. Targets that have been experimentally tested with inhibitors in K. pneumoniae are marked with an asterisk: LpxA 101 , 102 , LpxD 101 , FabB/FabH 103 , LpxC 104 , and MurG/MurE 105 . …”
Klebsiella pneumoniae (Kp) is a globally disseminated opportunistic pathogen that can cause life-threatening infections. It has been found as the culprit of many infection outbreaks in hospital environments, being particularly aggressive towards newborns and adults under intensive care. Many Kp strains produce extended-spectrum β-lactamases, enzymes that promote resistance against antibiotics used to fight these infections. The presence of other resistance determinants leading to multidrug-resistance also limit therapeutic options, and the use of ‘last-resort’ drugs, such as polymyxins, is not uncommon. The global emergence and spread of resistant strains underline the need for novel antimicrobials against Kp and related bacterial pathogens. To tackle this great challenge, we generated multiple layers of ‘omics’ data related to Kp and prioritized proteins that could serve as attractive targets for antimicrobial development. Genomics, transcriptomics, structuromic and metabolic information were integrated in order to prioritize candidate targets, and this data compendium is freely available as a web server. Twenty-nine proteins with desirable characteristics from a drug development perspective were shortlisted, which participate in important processes such as lipid synthesis, cofactor production, and core metabolism. Collectively, our results point towards novel targets for the control of Kp and related bacterial pathogens.
“… Figure 6 Venn diagram showing the number of unique and shared targets identified using the three different ranking strategies for drug targeting. Targets that have been experimentally tested with inhibitors in K. pneumoniae are marked with an asterisk: LpxA 101 , 102 , LpxD 101 , FabB/FabH 103 , LpxC 104 , and MurG/MurE 105 . …”
Klebsiella pneumoniae (Kp) is a globally disseminated opportunistic pathogen that can cause life-threatening infections. It has been found as the culprit of many infection outbreaks in hospital environments, being particularly aggressive towards newborns and adults under intensive care. Many Kp strains produce extended-spectrum β-lactamases, enzymes that promote resistance against antibiotics used to fight these infections. The presence of other resistance determinants leading to multidrug-resistance also limit therapeutic options, and the use of ‘last-resort’ drugs, such as polymyxins, is not uncommon. The global emergence and spread of resistant strains underline the need for novel antimicrobials against Kp and related bacterial pathogens. To tackle this great challenge, we generated multiple layers of ‘omics’ data related to Kp and prioritized proteins that could serve as attractive targets for antimicrobial development. Genomics, transcriptomics, structuromic and metabolic information were integrated in order to prioritize candidate targets, and this data compendium is freely available as a web server. Twenty-nine proteins with desirable characteristics from a drug development perspective were shortlisted, which participate in important processes such as lipid synthesis, cofactor production, and core metabolism. Collectively, our results point towards novel targets for the control of Kp and related bacterial pathogens.
“…3). This sequence is based on the cationic bactericidal peptide KFFKFFKFFK previously used by our group23 which was reported to have a direct activity against E. coli 24 and low eukaryotic toxicity and haemolysis.…”
A new category of phosphonium based cationic amphiphilic peptides has been developed and evaluated as potential antimicrobial peptides and cell penetrating peptides. The required building blocks were conveniently accessible from cysteine and could be applied in a solid phase peptide synthesis protocol for incorporation into peptide sequences. Evaluation of the antimicrobial properties and cellular toxicity of these phosphonium based peptides showed that these "soft" cationic side-chain containing peptides have poor antimicrobial properties and most of them were virtually non toxic (on HEK cells tested at 256 and 512 μM) and non-haemolytic (on horse erythrocytes tested at 512 μM), hinting at an interesting potential application as cell penetrating peptides. This possibility was evaluated using fluorescent peptide derivatives and showed that these phosphonium based peptide derivatives were capable of entering HEK cells and depending on the sequence confined to specific cellular areas.
“…The mechanisms employed by MAPs in crossing membranes are varied and dependent on the specific MAP and the target membrane . However, their OM penetrating ability has been exploited through conjugation as “vectors” to various “cargoes” for delivery into Gram-negative bacteria. ,− For example, a synthetic MAP has been used to deliver antisense peptide-nucleic acids for gene silencing into the cytoplasm of Gram-negative bacteria while various MAP-vancomycin conjugates have been used to repurpose vancomycin (a classically Gram-positive specific antibiotic that cannot cross the Gram-negative OM) into a Gram-negative antibiotic . MAP-Bicycle conjugates could therefore also be used to overcome the OM barrier.…”
Growing antibiotic resistance is rapidly threatening the efficacy of treatments for Gram-negative infections. Bicycle molecules, constrained bicyclic peptides from diverse libraries generated by bacteriophage display that bind with high affinity to a chosen target are a potential new class of antibiotics. The generally impermeable bacterial outer membrane currently limits the access of peptides to bacteria. The conjugation of membrane active peptides offers an avenue for outer membrane penetration. Here, we investigate which physicochemical properties of a specific membrane active peptide (MAP), derived from ixosin-B, could be tweaked to enhance the penetration of conjugates by generating multiple MAP-Bicycle conjugate variants. We demonstrate that charge and hydrophobicity are important factors, which enhance penetration and, therefore, antimicrobial potency. Interestingly, we show that induction of secondary structure, but not a change in amphipathicity, is vital for effective penetration of the Gram-negative outer membrane. These results offer insights into the ways vectors could be designed to deliver Bicycle molecules (and other cargos) through biological membranes.
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