Polymyxin B nonapeptide potentiates the eradication of Gram-negative bacterial persisters.

Antibiotic-resistant Gram-negative bacteria remain a globally leading cause of bacterial infection-associated mortality, and it is imperative to identify novel therapeutic strategies. Recently, the advantage of using antibacterials selective against Gram-negative bacteria has been demonstrated with polymyxins that specifically target the lipopolysaccharides of Gram-negative bacteria. However, the severe cytotoxicity of polymyxins limits their clinical use. Here, we demonstrate that polymyxin B nonapeptide (PMBN), a polymyxin B derivative without the terminal amino acyl residue, can significantly enhance the effectiveness of commonly used antibiotics against only Gram-negative bacteria and their persister cells. We show that although PMBN itself does not exhibit antibacterial activity or cytotoxicity well above the 100-fold minimum inhibitory concentration of polymyxin B, PMBN can increase the potency of co-treated antibiotics. We also demonstrate that using PMBN in combination with other antibiotics significantly reduces the frequency of resistant mutant formation. Together, this work provides evidence of the utilities of PMBN as a novel potentiator for antibiotics against Gram-negative bacteria and insights for the eradication of bacterial persister cells during antibiotic treatment. IMPORTANCE: The significance of our study lies in addressing the problem of antibiotic-resistant Gram-negative bacteria, which continue to be a global cause of mortality associated with bacterial infections. Therefore, identifying innovative therapeutic approaches is an urgent need. Recent research has highlighted the potential of selective antibacterials like polymyxins, which specifically target the lipopolysaccharides of Gram-negative bacteria. However, the clinical use of polymyxins is limited by their severe cytotoxicity. This study unveils the effectiveness of polymyxin B nonapeptide (PMBN) in significantly enhancing the eradication of persister cells in Gram-negative bacteria. Although PMBN itself does not exhibit antibacterial activity or cytotoxicity, it remarkably reduces persister cells during the treatment of antibiotics. Moreover, combining PMBN with other antibiotics reduces the emergence of resistant mutants. Our research emphasizes the utility of PMBN as a novel potentiator to decrease persister cells during antibiotic treatments for Gram-negative bacteria.

A novel antibiotic combination of linezolid and polymyxin B octapeptide PBOP against clinical Pseudomonas aeruginosa strains.

BACKGROUND: Antibiotic-resistant Gram-negative bacteria are becoming a major public health threat such as the important opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study investigated enhancement of the linezolid spectrum, which is normally used to treat Gram-positive bacteria, at inhibiting P. aeruginosa growth. METHODS: The checkerboard test or time-kill assay were carried out to determine the antibacterial effects of linezolid in cooperation with polymyxin B octapeptide PBOP (LP) against P. aeruginosa based on in vitro model. The protective effect of LP against P. aeruginosa infection was assessed based on a Caenorhabditis elegans (C. elegans) model. RESULTS: The synergistic activity and antibacterial effects were significantly increased against P. aeruginosa by LP treatment, while linezolid and PBOP as monotherapies exhibited no remarkably bactericidal activity against the clinical strains. Additionally, LP treatment modified biofilm production, morphology, swimming motility of P. aeruginosa, and protected C. elegans from P. aeruginosa infection. CONCLUSIONS: This research demonstrates that LP combination has significant synergistic activity against P. aeruginosa, and PBOP is potential to be an activity enhancer. Notably, this strategy improved the antibacterial activity spectrum of linezolid and other anti-Gram-positive agents and represents an effective choice to surmount the antibiotic resistance of bacteria in the long term.

A method for increasing electroporation competence of Gram-negative clinical isolates by polymyxin B nonapeptide.

The study of clinically relevant bacterial pathogens relies on molecular and genetic approaches. However, the generally low transformation frequency among natural isolates poses technical hurdles to widely applying common methods in molecular biology, including transformation of large constructs, chromosomal genetic manipulation, and dense mutant library construction. Here we demonstrate that culturing clinical isolates in the presence of polymyxin B nonapeptide (PMBN) improves their transformation frequency via electroporation by up to 100-fold in a dose-dependent and reversible manner. The effect was observed for PMBN-binding uropathogenic Escherichia coli (UPEC) and Salmonella enterica strains but not naturally polymyxin resistant Proteus mirabilis. Using our PMBN electroporation method we show efficient delivery of large plasmid constructs into UPEC, which otherwise failed using a conventional electroporation protocol. Moreover, we show a fivefold increase in the yield of engineered mutant colonies obtained in S. enterica with the widely used lambda-Red recombineering method, when cells are cultured in the presence of PMBN. Lastly, we demonstrate that PMBN treatment can enhance the delivery of DNA-transposase complexes into UPEC and increase transposon mutant yield by eightfold when constructing Transposon Insertion Sequencing (TIS) libraries. Therefore, PMBN can be used as a powerful electropermeabilisation adjuvant to aid the delivery of DNA and DNA-protein complexes into clinically important bacteria.

Ceftazidime-avibactam activity against a challenge set of carbapenem-resistant Enterobacterales: Ompk36 L3 alterations and ß-lactamases with ceftazidime hydrolytic activity lead to elevated MIC values.

INTRODUCTION: This study examined ceftazidime-avibactam activity against carbapenem-resistant Enterobacterales (CRE) clinical isolates and resistance mechanisms among non-metallo ß-lactamase (MBL) producers displaying ceftazidime-avibactam MIC values at 4 mg/L. METHODS: CRE isolates (286 of 8161 Enterobacterales) collected in Asia-Pacific, Europe and Latin America during 2016 were screened for carbapenemase genes. Selected isolates were susceptibility tested for ceftazidime-avibactam in the presence or absence of phenylalanine-arginyl ß-naphthylamide (PAßN) and polymyxin B nonapeptide (PMBN). Genome sequences were investigated for the integrity of outer membrane protein (OMP) genes and multilocus sequence typing. qRT-PCR assays were conducted to determine expression of acrA, ampC, and OMP genes. RESULTS: Ceftazidime-avibactam inhibited 99.2% of the Enterobacterales, 22 (78.7%) of the 286 CRE and 226 (100%) non-MBL producers. Among carbapenemase producers (85.3%; 244 of 286), the most common gene was blaKPC (76 blaKPC-3 and 46 blaKPC-2), followed by blaOXA-48-like (60 isolates) and blaNDM (37). Ceftazidime-avibactam MIC values at 4 mg/L were noted among 14 Klebsiella pneumoniae (13 carrying blaKPC and 1 blaCTX-M-15) mostly from Italy and Brazil and 1 Klebsiella aerogenes overexpressing ampC. PAßN did not significantly decrease ceftazidime-avibactam results, but adding PMBN did significantly decrease the MIC results for the combination. All K. pneumoniae isolates had a premature stop codon at OmpK35 and most isolates had L3 alterations of OmpK36, low expression of this gene, or OmpC disruption (K. aerogenes). Nine K. pneumoniae isolates belonged to clonal complex 258 and displayed intrahospital clonality. CONCLUSION: Ceftazidime-avibactam is an important addition to the armamentarium against multidrug-resistant organisms, and elevated MIC results for this combination seem to be associated with L3 OmpK36 alterations and ß-lactamases able to hydrolyze ceftazidime.

Expansion of antibacterial spectrum of xanthorrhizol against Gram-negatives in combination with PMBN and food-grade antimicrobials.

Xanthorrhizol (XTZ), isolated from Curcuma xanthorrhiza, has potent antifungal and antibacterial activity. It shows very strong activity against Gram-positive bacteria, such as Streptococcus mutans and Staphylococcus aureus, but is generally not active against Gram-negative bacteria. In this study, we explored the possibility of using a combination strategy for expanding the antimicrobial spectrum of XTZ against Gram-negative bacteria. To take advantage of XTZ being a food-grade material, 10 food-grade or generally recognized as safe (GRAS) antimicrobial compounds with low toxicities were selected for combination therapy. In addition, polymyxin B nonapeptide (PMBN), which is less toxic than polymyxin B, was also selected as an outer membrane permeabilizer. The antibacterial activity of various double or triple combinations with or without XTZ were assayed in vitro against four Gram-negative bacterial species (Escherichia coli, Salmonella enterica serovar Typhi, Salmonella enterica serovar Typhimurium, and Vibrio cholerae), with synergistic combinations exhibiting clear activity subjected to further screening. The combinations with the greatest synergism were XTZ + PMBN + nisin, XTZ + PMBN + carvacrol, and XTZ + PMBN + thymol. These combinations also showed potent antimicrobial activity against Shigella spp., Yersinia enterocolitica, and Acinetobacter baumannii. In time-kill assays, the three combinations achieved complete killing of E. coli within 2 h, and S. Typhi and V. cholera within 15 min. This is the first report on expanding the activity spectrum of XTZ against Gram-negative bacteria through combination with PMBN and food-grade or GRAS substances, with the resulting findings being particularly useful for increasing the industrial and medical applications of XTZ.

Development of dilipid polymyxins: Investigation on the effect of hydrophobicity through its fatty acyl component.

Continuous development of new antibacterial agents is necessary to counter the problem of antimicrobial resistance. Polymyxins are considered as drugs of last resort to combat multidrug-resistant Gram-negative pathogens. Structural optimization of polymyxins requires an in-depth understanding of its structure and how it relates to its antibacterial activity. Herein, the effect of hydrophobicity was explored by adding a secondary fatty acyl component of varying length onto the polymyxin structure at the amine side-chain of l-diaminobutyric acid at position 1, resulting to the development of dilipid polymyxins. The incorporation of an additional lipid was found to confer polymyxin activity against Gram-positive bacteria, to which polymyxins are inherently inactive against. The dilipid polymyxins showed selective antibacterial activity against Pseudomonas aeruginosa. Moreover, dilipid polymyxin 1 that consists of four carbon-long aliphatic lipids displayed the ability to enhance the antibacterial potency of other antibiotics in combination against P. aeruginosa, resembling the adjuvant activity of the well-known outer membrane permeabilizer polymyxin B nonapeptide (PMBN). Interestingly, our data revealed that dilipid polymyxin 1 and PMBN are substrates for the MexAB-OprM efflux system, and therefore are affected by efflux. In contrast, dilipid polymyxin analogs that consist of longer lipids and colistin were not affected by efflux, suggesting that the lipid component of polymyxin plays an important role in resisting active efflux. Our work described herein provides an understanding to the polymyxin structure that may be used to usher the development of enhanced polymyxin analogs.

Synthetic Immunotherapeutics against Gram-negative Pathogens.

While traditional drug discovery continues to be an important platform for the search of new antibiotics, alternative approaches should also be pursued to complement these efforts. We herein designed a class of molecules that decorate bacterial cell surfaces with the goal of re-engaging components of the immune system toward Escherichia coli and Pseudomonas aeruginosa. More specifically, conjugates were assembled using polymyxin B (an antibiotic that inherently attaches to the surface of Gram-negative pathogens) and antigenic epitopes that recruit antibodies found in human serum. We established that the spacer length played a significant role in hapten display within the bacterial cell surface, a result that was confirmed both experimentally and via molecular dynamics simulations. Most importantly, we demonstrated the specific killing of bacteria by our agent in the presence of human serum. By enlisting the immune system, these agents have the potential to pave the way for a potent antimicrobial modality.

Comparison of the composition and in vitro activity of polymyxin B products.

A number of companies manufacture polymyxin B using United States Pharmacopeia (USP) metrics, rather than chemical composition, to report biological activity. Given that polymyxin B contains several different components, it is unknown whether pharmacokinetic and pharmacodynamic variability exists between the different brands and whether USP metrics capture this variability. Here we investigated the composition of polymyxin B obtained from four manufacturers (Sigma-Aldrich, AK Scientific, USP and MP Biomedicals) and evaluated their rate and extent of killing against multidrug-resistant Acinetobacter baumannii and Klebsiella pneumoniae using in vitro static time-kill experiments. Ultraviolet (UV) fingerprinting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed similarities and differences between component distributions. The significant differences between products, based on UV fingerprinting and LC-MS/MS, did not translate into pharmacodynamic differences at the three concentrations evaluated. The aggregate polymyxin B concentration, rather than that of the individual components, influences overall bacterial killing.

A Fluorescent Probe Distinguishes between Inhibition of Early and Late Steps of Lipopolysaccharide Biogenesis in Whole Cells.

Lipopolysaccharide (LPS) biogenesis in Gram-negative organisms involves its biosynthesis in the cytoplasm and subsequent transport across three cellular compartments to the cell surface. We developed a fluorescent probe that allows us to determine the spatial distribution of LPS in whole cells. We show that polymyxin B nonapeptide (PMBN) containing a dansyl fluorophore specifically binds to LPS in membranes. We show that this probe detects decreases in LPS levels on the cell surface when LPS biosynthesis is inhibited at an early step. We also can detect accumulation of LPS in particular subcellular locations when LPS assembly is blocked during transport, allowing us to differentiate inhibitors targeting early and late stages of LPS biogenesis.

Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B.

The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity-toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure-activity and structure-toxicity studies set the stage for further improvements to the polymyxin class of antibiotics.

Tryptophan-containing lipopeptide antibiotics derived from polymyxin B with activity against Gram positive and Gram negative bacteria.

Resistance to all known antibiotics is a growing concern worldwide, and has renewed the interest in antimicrobial peptides, a structurally diverse class of amphipathic molecules that essentially act on the bacterial membrane. Propelled by the antimicrobial potential of this compound class, we have designed three new lipopeptides derived from polymyxin B, sp-34, sp-96 and sp-100, with potent antimicrobial activity against both Gram positive and Gram negative bacteria. The three peptides bind with high affinity to lipopolysaccharide as demonstrated by monolayer penetration and dansyl-displacement. The interaction with the cytoplasmic membrane has been elucidated by biophysical experiments with model membranes of POPG or POPE/POPG (6:4), mimicking the Gram positive and Gram negative bacterial membrane. Trp-based fluorescence experiments including steady-state, quenching, anisotropy and FRET, reveal selectivity for anionic phospholipids and deep insertion into the membrane. All three lipopeptides induce membrane fusion and leakage from anionic vesicles, a process that is favored by the presence of POPE. The molecules bind to zwitterionic POPC vesicles, a model of the eukaryotic membrane, but in a different way, with lower affinity, less penetration into the bilayer and no fusion or permeabilization of the membrane. Results in model membranes are consistent with flow cytometry experiments in Escherichia coli and Staphylococcus aureus using a membrane potential sensitive dye (bis-oxonol) and a nucleic acid dye (propidium iodide), suggesting that the mechanism of action is based on membrane binding and collapse of membrane integrity by depolarization and permeabilization.

Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using Rationally Designed Fluorescent Probes.

Polymyxins are cyclic lipopeptide antibiotics that serve as a last line of defense against Gram-negative bacterial superbugs. However, the extensive accumulation of polymyxins in renal tubular cells can lead to nephrotoxicity, which is the major dose-limiting factor in clinical use. In order to gain further insights into the mechanism of polymyxin-induced nephrotoxicity, we have rationally designed novel fluorescent polymyxin probes to examine the localization of polymyxins in rat renal tubular (NRK-52E) cells. Our design strategy focused on incorporating a dansyl fluorophore at the hydrophobic centers of the polymyxin core structure. To this end, four novel regioselectively labeled monodansylated polymyxin B probes (MIPS-9541, MIPS-9542, MIPS-9543, and MIPS-9544) were designed, synthesized, and screened for their antimicrobial activities and apoptotic effects against rat kidney proximal tubular cells. On the basis of the assessment of antimicrobial activities, cellular uptake, and apoptotic effects on renal tubular cells, incorporation of a dansyl fluorophore at either position 6 or 7 (MIPS-9543 and MIPS-9544, respectively) of the polymyxin core structure appears to be an appropriate strategy for generating representative fluorescent polymyxin probes to be utilized in intracellular imaging and mechanistic studies. Furthermore, confocal imaging experiments utilizing these probes showed evidence of partial colocalization of the polymyxins with both the endoplasmic reticulum and mitochondria in rat renal tubular cells. Our results highlight the value of these new fluorescent polymyxin probes and provide further insights into the mechanism of polymyxin-induced nephrotoxicity.

Microbiological Assessment of Polymyxin B Components Tested Alone and in Combination.

We investigated the antimicrobial activity of four polymyxin B components, B1, B2, B3, and isoleucine (Ile)-B1, individually and in combination. B3 was the most active agent against all organisms tested except Acinetobacter baumannii, for which Ile-B1 was most active. One combination met the criteria for synergy, B3 plus Ile-B1. No combinations exhibited antagonism. The dominant components of polymyxin B products (B1 and B2) were associated with the lowest probability of improved antibacterial activity when combined.

Importance of Real-Time Assays To Distinguish Multidrug Efflux Pump-Inhibiting and Outer Membrane-Destabilizing Activities in Escherichia coli.

UNLABELLED: The constitutively expressed AcrAB multidrug efflux system of Escherichia coli shows a high degree of homology with the normally silent AcrEF system. Exposure of a strain with acrAB deleted to antibiotic selection pressure frequently leads to the insertion sequence-mediated activation of the homologous AcrEF system. In this study, we used strains constitutively expressing either AcrAB or AcrEF from their normal chromosomal locations to resolve a controversy about whether phenylalanylarginine ß-naphthylamide (PAßN) inhibits the activities of AcrAB and AcrEF and/or acts synergistically with antibiotics by destabilizing the outer membrane permeability barrier. Real-time efflux assays allowed a clear distinction between the efflux pump-inhibiting activity of PAßN and the outer membrane-destabilizing action of polymyxin B nonapeptide (PMXBN). When added in equal amounts, PAßN, but not PMXBN, strongly inhibited the efflux activities of both AcrAB and AcrEF pumps. In contrast, when outer membrane destabilization was assessed by the nitrocefin hydrolysis assay, PMXBN exerted a much greater damaging effect than PAßN. Strong action of PAßN in inhibiting efflux activity compared to its weak action in destabilizing the outer membrane permeability barrier suggests that PAßN acts mainly by inhibiting efflux pumps. We concluded that at low concentrations, PAßN acts specifically as an inhibitor of both AcrAB and AcrEF efflux pumps; however, at high concentrations, PAßN in the efflux-proficient background not only inhibits efflux pump activity but also destabilizes the membrane. The effects of PAßN on membrane integrity are compounded in cells unable to extrude PAßN. IMPORTANCE: The increase in multidrug-resistant bacterial pathogens at an alarming rate has accelerated the need for implementation of better antimicrobial stewardship, discovery of new antibiotics, and deeper understanding of the mechanism of drug resistance. The work carried out in this study highlights the importance of employing real-time fluorescence-based assays in differentiating multidrug efflux-inhibitory and outer membrane-destabilizing activities of antibacterial compounds.

Synthesis of a polymyxin derivative for photolabeling studies in the gram-negative bacterium Escherichia coli.

The antimicrobial activity of polymyxins against Gram-negative bacteria has been known for several decades, but the mechanism of action leading to cell death has not been fully explored. A key step after binding of the antibiotic to lipopolysaccharide (LPS) exposed at the cell surface is 'self-promoted uptake' across the outer membrane (OM), in which the antibiotic traverses the asymmetric LPS-phospholipid bilayer before reaching the periplasm and finally targeting and disrupting the bacterial phospholipid inner membrane. The work described here was prompted by the hypothesis that polymyxins might interact with proteins in the OM, as part of their self-promoted uptake and permeabilizing effects. One way to test this is through photolabeling experiments. We describe the design and synthesis of a photoprobe based upon polymyxin B, containing photoleucine and an N-acyl group with a terminal alkyne suitable for coupling to a biotin tag using click chemistry. The resulting photoprobe retains potent antimicrobial activity, and in initial photolabeling experiments with Escherichia coli ATCC25922 is shown to photolabel several OM proteins. This photoprobe might be a valuable tool in more detailed studies on the mechanism of action of this family of antibiotics.

The antibacterial effect of nitric oxide against ESBL-producing uropathogenic E. coli is improved by combination with miconazole and polymyxin B nonapeptide.

BACKGROUND: Nitric oxide (NO) is produced as part of the host immune response to bacterial infections, including urinary tract infections. The enzyme flavohemoglobin, coded by the hmp gene, is involved in protecting bacterial cells from the toxic effects of NO and represents a potentially interesting target for development of novel treatment concepts against resistant uropathogenic bacteria. The aim of the present study was to investigate if the in vitro antibacterial effects of NO can be enhanced by pharmacological modulation of the enzyme flavohemoglobin. RESULTS: Four clinical isolates of multidrug-resistant extended-spectrum ß-lactamase (ESBL)-producing uropathogenic E. coli were included in the study. It was shown that the NO-donor substance DETA/NO, but not inactivated DETA/NO, caused an initial growth inhibition with regrowth noted after 8 h of exposure. An hmp-deficient strain showed a prolonged growth inhibition in response to DETA/NO compared to the wild type. The imidazole antibiotic miconazole, that has been shown to inhibit bacterial flavohemoglobin activity, prolonged the DETA/NO-evoked growth inhibition. When miconazole was combined with polymyxin B nonapeptide (PMBN), in order to increase the bacterial wall permeability, DETA/NO caused a prolonged bacteriostatic response that lasted for up to 24 h. CONCLUSION: An NO-donor in combination with miconazole and PMBN showed enhanced antimicrobial effects and proved effective against multidrug-resistant ESBL-producing uropathogenic E. coli.

Probing the penetration of antimicrobial polymyxin lipopeptides into gram-negative bacteria.

The dry antibiotic development pipeline coupled with the emergence of multidrug resistant Gram-negative 'superbugs' has driven the revival of the polymyxin lipopeptide antibiotics. Polymyxin resistance implies a total lack of antibiotics for the treatment of life-threatening infections. The lack of molecular imaging probes that possess native polymyxin-like antibacterial activity is a barrier to understanding the resistance mechanisms and the development of a new generation of polymyxin lipopeptides. Here we report the regioselective modification of the polymyxin B core scaffold at the N-terminus with the dansyl fluorophore to generate an active probe that mimics polymyxin B pharmacologically. Time-lapse laser scanning confocal microscopy imaging of the penetration of probe (1) into Gram-negative bacterial cells revealed that the probe initially accumulates in the outer membrane and subsequently penetrates into the inner membrane and finally the cytoplasm. The implementation of this polymyxin-mimetic probe will advance the development of platforms for the discovery of novel polymyxin lipopeptides with efficacy against polymyxin-resistant strains.

Early prediction of polymyxin-induced nephrotoxicity with next-generation urinary kidney injury biomarkers.

Despite six decades of clinical experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of standard of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) derivative with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathological and biomarker analysis of PMBN, an important test of the hypothesis that fatty acid modifications and charge reductions in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathological injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clinical standards of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathological evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.

Polymyxin derivatives: a patent evaluation (WO2012168820).

The patent application WO201268820 claims a new class of polymyxin derivatives with potent antibacterial activity, especially toward Gram-negative pathogens. Compared to parent polymyxin B (PMB), the new derivatives have more potent antibacterial activity, as well as reduced cytotoxicity against human renal cells.

Mimicking an antimicrobial peptide polymyxin B by use of cyclodextrin.

Cyclodextrin derivatives prepared to mimic a membrane active antibacterial peptide polymyxin B strongly permeabilized bacterial membrane and inhibited bacterial proliferation.