Improvement of Charcot-Marie-Tooth Phenotype with a Nanocomplex Treatment in Two Transgenic Models of CMT1A.

Curcumin has been shown to exert beneficial effects in peripheral neuropathies. Despite its known biological activities, curcumin has unfavorable pharmacokinetics. Its instability has been linked to its failure in clinical trials of curcumin for the treatment of human pathologies. For this reason, we developed curcumin-loaded cyclodextrin/cellulose nanocrystals (NanoCur) to improve its pharmacokinetics. The present study aims to assess the potency of a low dose of NanoCur in 2 Charcot-Marie-Tooth disease type 1A (CMT1A) rodent models at different stages of the disease. The efficiency of NanoCur is also compared to that of Theracurmin (Thera), a commercially available curcumin formulation. The toxicity of a short-term and chronic exposure to the treatment is investigated both in vitro and in vivo, respectively. Furthermore, the entry route, the mechanism of action and the effect on the nerve phenotype are dissected in this study. Overall, the data support an improvement in sensorimotor functions, associated with amelioration in peripheral myelination in NanoCur-treated animals; an effect that was not evident in the Thera-treated group. That was combined with a high margin of safety both in vivo and in vitro. Furthermore, NanoCur appears to inhibit inflammatory pathways that normally include macrophage recruitment to the diseased nerve. This study shows that NanoCur shows therapeutic benefits with minimal systemic toxicity, suggesting that it is a potential therapeutic candidate for CMT1A and, possibly, for other neuropathies.

Easy and versatile cellulosic support inhibiting broad spectrum strains: synergy between photodynamic antimicrobial therapy and polymyxin B.

Despite advances achieved in the health field over the last decade, infections caused by resistant bacterial strains are an increasingly important societal issue that needs to be addressed. New approaches have already been developed to overcome this problem. Photodynamic antimicrobial chemotherapy (PACT) could provide a promising alternative method to eradicate microbes. This approach has already inspired the development of innovative surfaces. Interesting results were achieved against Gram-positive bacteria, but it also appeared that Gram-negative strains, especially Pseudomonas aeruginosa, were less sensitive to PACT. However, materials coated with cationic porphyrins have already proven their wide-spectrum activity, but these materials were not suitable for industrial-scale production. The main aim of this work was the design of a large-scale evolutionary material based on PACT and antibiotic prophylaxis. Transparent regenerated cellulose has been simply impregnated with a usual cationic porphyrin (N-methylpyridyl) and an antimicrobial peptide (polymyxin B). In addition to its photophysical properties, this film exhibited a wide-spectrum bactericidal activity over 4 days despite daily application of fresh bacterial inoculums. The efficiency of PACT and polymyxin B combination could help to reduce the emergence of bacterial multi-resistant strains and we believe that this kind of material would provide an excellent opportunity to prevent bacterial contamination of bandages or packaging.

Hydrophilic Biocompatible Fluorescent Organic Nanoparticles as Nanocarriers for Biosourced Photosensitizers for Photodynamic Therapy.

Most photosensitizers of interest for photodynamic therapy-especially porphyrinoids and chlorins-are hydrophobic. To circumvent this difficulty, the use of nanocarriers is an attractive strategy. In this perspective, we have developed highly water-soluble and biocompatible fluorescent organic nanoparticles (FONPs) made from citric acid and diethyltriamine which are then activated by ethlynene diamine as nanoplatforms for efficient photosensitizers (PSs). Purpurin 18 (Pp18) was selected as a biosourced chlorin photosensitizer combining the efficient single oxygen generation ability and suitable absorption in the biological spectral window. The simple reaction of activated FONPs with Pp18, which contains a reactive anhydride ring, yielded nanoparticles containing both Pp18 and Cp6 derivatives. These functionalized nanoparticles combine solubility in water, high singlet oxygen generation quantum yield in aqueous media (0.72) and absorption both in the near UV region (FONPS) and in the visible region (Soret band approximately 420 nm as well as Q bands at 500 nm, 560 nm, 660 nm and 710 nm). The functionalized nanoparticles retain the blue fluorescence of FONPs when excited in the near UV region but also show deep-red or NIR fluorescence when excited in the visible absorption bands of the PSs (typically at 520 nm, 660 nm or 710 nm). Moreover, these nanoparticles behave as efficient photosensitizers inducing colorectal cancer cell (HCT116 and HT-29 cell lines) death upon illumination at 650 nm. Half maximal inhibitory concentration (IC50) values down to, respectively, 0.04 and 0.13 nmol/mL were observed showing the potential of FONPs[Cp6] for the PDT treatment of cancer. In conclusion, we have shown that these novel biocompatible nanoparticles, which can be elaborated from biosourced components, both show deep-red emission upon excitation in the red region and are able to produce singlet oxygen with high efficiency in aqueous environments. Moreover, they show high PDT efficiency on colorectal cancer cells upon excitation in the deep red region. As such, these functional organic nanoparticles hold promise both for PDT treatment and theranostics.

Enforcing Local DNA Kinks by Sequence-Selective Trisintercalating Oligopeptides of a Tricationic Porphyrin: A Polarizable Molecular Dynamics Study.

Bisacridinyl-bisarginyl porphyrin (BABAP) is a trisintercalating derivative of a tricationic porphyrin, formerly designed and synthesized in order to selectively target and photosensitize the ten-base pair palindromic sequence d(CGGGCGCCCG)2 . We resorted to the previously derived (Far et al., 2004) lowest energy-minimized (EM) structure of the BABAP complex with this sequence as a starting point. We performed polarizable molecular dynamics (MD) on this complex. It showed, over a 150 ns duration, the persistent binding of the Arg side-chain on each BABAP arm to the two G bases upstream from the central porphyrin intercalation site. We subsequently performed progressive shortenings of the connector chain linking the Arg-Gly backbone to the acridine, from n=6 methylenes to 4, followed by removal of the Gly backbone and further connector shortenings, from n=4 to n=1. These resulted into progressive deformations ('kinks') of the DNA backbone. In its most accented kinked structure, the DNA backbone was found to have a close overlap with that of DNA bound to Cre recombinase, with, at the level of one acridine intercalation site, negative roll and positive tilt values consistent with those experimentally found for this DNA at its own kinked dinucleotide sequence. Thus, in addition to their photosensitizing properties, some BABAP derivatives could induce sequence-selective, controlled DNA deformations, which are targets for cleavage by endonucleases or for repair enzymes.

A Review of Phototoxic Plants, Their Phototoxic Metabolites, and Possible Developments as Photosensitizers.

This study provides a comprehensive overview of the current knowledge regarding phototoxic terrestrial plants and their phototoxic and photosensitizing metabolites. Within the 435,000 land plant species, only around 250 vascular plants have been documented as phototoxic or implicated in phototoxic occurrences in humans and animals. This work compiles a comprehensive catalog of these phototoxic plant species, organized alphabetically based on their taxonomic family. The dataset encompasses meticulous details including taxonomy, geographical distribution, vernacular names, and information on the nature and structure of their phototoxic and photosensitizing molecule(s). Subsequently, this study undertook an in-depth investigation into phototoxic molecules, resulting in the compilation of a comprehensive and up-to-date list of phytochemicals exhibiting phototoxic or photosensitizing activity synthesized by terrestrial plants. For each identified molecule, an extensive review was conducted, encompassing discussions on its phototoxic activity, chemical family, occurrence in plant families or species, distribution within different plant tissues and organs, as well as the biogeographical locations of the producer species worldwide. The analysis also includes a thorough discussion on the potential use of these molecules for the development of new photosensitizers that could be used in topical or injectable formulations for antimicrobial and anticancer phototherapy as well as manufacturing of photoactive devices.

Natural Chalcones and Derivatives in Colon Cancer: Pre-Clinical Challenges and the Promise of Chalcone-Based Nanoparticles.

Colon cancer poses a complex and substantial global health challenge, necessitating innovative therapeutic approaches. Chalcones, a versatile class of compounds with diverse pharmacological properties, have emerged as promising candidates for addressing colon cancer. Their ability to modulate pivotal signaling pathways in the development and progression of colon cancer makes them invaluable as targeted therapeutics. Nevertheless, it is crucial to recognize that although chalcones exhibit promise, further pre-clinical studies are required to validate their efficacy and safety. The journey toward effective colon cancer treatment is multifaceted, involving considerations such as optimizing the sequencing of therapeutic agents, comprehending the resistance mechanisms, and exploring combination therapies incorporating chalcones. Furthermore, the integration of nanoparticle-based drug delivery systems presents a novel avenue for enhancing the effectiveness of chalcones in colon cancer treatment. This review delves into the mechanisms of action of natural chalcones and some derivatives. It highlights the challenges associated with their use in pre-clinical studies, while also underscoring the advantages of employing chalcone-based nanoparticles for the treatment of colon cancer.

The Promise of Piperine in Cancer Chemoprevention.

Cancer, characterized by the unregulated growth and dissemination of malignantly transformed cells, presents a significant global health challenge. The multistage process of cancer development involves intricate biochemical and genetic alterations within target cells. Cancer chemoprevention has emerged as a vital strategy to address this complex issue to mitigate cancer's impact on healthcare systems. This approach leverages pharmacologically active agents to block, suppress, prevent, or reverse invasive cancer development. Among these agents, piperine, an active alkaloid with a wide range of therapeutic properties, including antioxidant, anti-inflammatory, and immunomodulatory effects, has garnered attention for its potential in cancer prevention and treatment. This comprehensive review explores piperine's multifaceted role in inhibiting the molecular events and signaling pathways associated with various stages of cancer development, shedding light on its promising prospects as a versatile tool in cancer chemoprevention. Furthermore, the review will also delve into how piperine enhances the effectiveness of conventional treatments such as UV-phototherapy and TRAIL-based therapy, potentially synergizing with existing therapeutic modalities to provide more robust cancer management strategies. Finally, a crucial perspective of the long-term safety and potential side effects of piperine-based therapies and the need for clinical trials is also discussed.

Thermodynamic and structural properties of lipid-photosensitizer conjugates mixed with phospholipids: Impact on the formation and stability of nano-assemblies.

The photosensitizer Phenalenone (PN) was grafted with one or two lipid (C18) chains to form pure nano-assemblies or mixed lipid vesicles suitable for photodynamic therapy. Mixtures of PN-C18 conjugates with stearoyl-oleoyl phosphatidylcholine (SOPC) form vesicles that disintegrate into bilayer sheets as the concentration of PN-C18 conjugates increases. We hypothesized that PN-C18 conjugates control the thermodynamic and structural properties of the mixtures and induce the disintegration of vesicles due to PN π-π-interactions. Monolayers were analyzed by surface pressure and grazing incidence X-ray diffraction (GIXD) measurements, and vesicles by differential scanning calorimetry and cryo-TEM. The results showed that PN-triazole-C18 (1A) and PN-NH-C18 (1B) segregate from the phospholipid domains. PN-(C18)2 (conjugate 2) develops favorable interactions with SOPC and distearoyl-phosphatidylcholine (DSPC). GIXD demonstrates the contribution of SOPC to the structuring of conjugate 2 and the role of the major component in controlling the structural properties of DSPC-conjugate 2 mixtures. Above 10 mol% conjugate 2 in SOPC vesicles, the coexistence of domains with different molecule packing leads to conjugate segregation, vesicle deformation, and the formation of small bilayer discs stabilized by the inter-bilayer π-π stacking of PN molecules.

Polyphenol-Based Nanoparticles: A Promising Frontier for Enhanced Colorectal Cancer Treatment.

Colorectal cancer (CRC) poses a significant challenge in healthcare, necessitating the exploration of novel therapeutic strategies. Natural compounds such as polyphenols with inherent anticancer properties have gained attention as potential therapeutic agents. This review highlights the need for novel therapeutic approaches in CRC, followed by a discussion on the synthesis of polyphenols-based nanoparticles. Various synthesis techniques, including dynamic covalent bonding, non-covalent bonding, polymerization, chemical conjugation, reduction, and metal-polyphenol networks, are explored. The mechanisms of action of these nanoparticles, encompassing passive and active targeting mechanisms, are also discussed. The review further examines the intrinsic anticancer activity of polyphenols and their enhancement through nano-based delivery systems. This section explores the natural anticancer properties of polyphenols and investigates different nano-based delivery systems, such as micelles, nanogels, liposomes, nanoemulsions, gold nanoparticles, mesoporous silica nanoparticles, and metal-organic frameworks. The review concludes by emphasizing the potential of nanoparticle-based strategies utilizing polyphenols for CRC treatment and highlights the need for future research to optimize their efficacy and safety. Overall, this review provides valuable insights into the synthesis, mechanisms of action, intrinsic anticancer activity, and enhancement of polyphenols-based nanoparticles for CRC treatment.

Shining a Light on Prostate Cancer: Photodynamic Therapy and Combination Approaches.

Prostate cancer is a major health concern worldwide, and current treatments, such as surgery, radiation therapy, and chemotherapy, are associated with significant side effects and limitations. Photodynamic therapy (PDT) is a promising alternative that has the potential to provide a minimally invasive and highly targeted approach to treating prostate cancer. PDT involves the use of photosensitizers (PSs) that are activated by light to produce reactive oxygen species (ROS), which can induce tumor cell death. There are two main types of PSs: synthetic and natural. Synthetic PSs are classified into four generations based on their structural and photophysical properties, while natural PSs are derived from plant and bacterial sources. Combining PDT with other therapies, such as photothermal therapy (PTT), photoimmunotherapy (PIT), and chemotherapy (CT), is also being explored as a way to improve its efficacy. This review provides an overview of conventional treatments for prostate cancer, the underlying principles of PDT, and the different types of PSs used in PDT as well as ongoing clinical studies. It also discusses the various forms of combination therapy being explored in the context of PDT for prostate cancer, as well as the challenges and opportunities associated with this approach. Overall, PDT has the potential to provide a more effective and less invasive treatment option for prostate cancer, and ongoing research is aimed at improving its selectivity and efficacy in clinical settings.

Xylan-Porphyrin Hydrogels as Light-Triggered Gram-Positive Antibacterial Agents.

In the present work, we report on the synthesis of light-triggered antibacterial hydrogels, based on xylan chains covalently bound to meso-tetra(4-carboxyphenyl)porphyrin (TCPP). Not only does TCPP act as a photosensitizer efficient against Gram-positive bacteria, but it also serves as a cross-linking gelator, enabling the simple and easy building of xylan conjugate hydrogels. The hydrogels were characterized by infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), along with swelling and rheological tests. The antimicrobial activity of the hydrogels was tested under visible light irradiation against two Gram-positive bacterial strains, Staphylococcus aureus and Bacillus cereus. The preliminary results showed an interesting activity on these bacteria, indicating that these hydrogels could be of great potential in the treatment of skin bacterial infections with this species by photodynamic antimicrobial chemotherapy (PACT).

First Example of a Heptazine-Porphyrin Dyad; Synthesis and Spectroscopic Properties.

We have prepared the first example of a porphyrin linked to an heptazine photoactive antenna. The two entities, linked with an alkyl spacer, demonstrate the activity of both active moieties. While they behave electrochemically independantly, on the other hand the spectroscopy shows the existence of energy transfer between both partners.

Coherent anti-Stokes Raman scattering cell imaging and segmentation with unsupervised data analysis.

Coherent Raman imaging has been extensively applied to live-cell imaging in the last 2 decades, allowing to probe the intracellular lipid, protein, nucleic acid, and water content with a high-acquisition rate and sensitivity. In this context, multiplex coherent anti-Stokes Raman scattering (MCARS) microspectroscopy using sub-nanosecond laser pulses is now recognized as a mature and straightforward technology for label-free bioimaging, offering the high spectral resolution of conventional Raman spectroscopy with reduced acquisition time. Here, we introduce the combination of the MCARS imaging technique with unsupervised data analysis based on multivariate curve resolution (MCR). The MCR process is implemented under the classical signal non-negativity constraint and, even more originally, under a new spatial constraint based on cell segmentation. We thus introduce a new methodology for hyperspectral cell imaging and segmentation, based on a simple, unsupervised workflow without any spectrum-to-spectrum phase retrieval computation. We first assess the robustness of our approach by considering cells of different types, namely, from the human HEK293 and murine C2C12 lines. To evaluate its applicability over a broader range, we then study HEK293 cells in different physiological states and experimental situations. Specifically, we compare an interphasic cell with a mitotic (prophase) one. We also present a comparison between a fixed cell and a living cell, in order to visualize the potential changes induced by the fixation protocol in cellular architecture. Next, with the aim of assessing more precisely the sensitivity of our approach, we study HEK293 living cells overexpressing tropomyosin-related kinase B (TrkB), a cancer-related membrane receptor, depending on the presence of its ligand, brain-derived neurotrophic factor (BDNF). Finally, the segmentation capability of the approach is evaluated in the case of a single cell and also by considering cell clusters of various sizes.

Antibacterial Photodynamic Therapy in the Near-Infrared Region with a Targeting Antimicrobial Peptide Connected to a π-Extended Porphyrin.

The increase of antimicrobial resistance to conventional antibiotics is worldwide a major health problem that requires the development of new bactericidal strategies. Antimicrobial photodynamic therapy (a-PDT) that generates reactive oxygen species acting on multiple cellular targets is unlikely to induce bacterial resistance. This localized treatment requires, for safe and efficient treatment of nonsuperficial infections, a targeting photosensitizer excited in the near IR. To this end, a new conjugate consisting of an antimicrobial peptide linked to a π-extended porphyrin photosensitizer was designed for a-PDT. Upon irradiation at 720 nm, the conjugate has shown at micromolar concentration strong bactericidal action on both Gram-positive and Gram-negative bacteria. Moreover, this conjugate allows one to reach a low minimum bactericidal concentration with near IR excitation without inducing toxicity to skin cells.

Synthesis and Investigation of Flavanone Derivatives as Potential New Anti-Inflammatory Agents.

Flavonoids are polyphenols with broad known pharmacological properties. A series of 2,3-dihydroflavanone derivatives were thus synthesized and investigated for their anti-inflammatory activities. The target flavanones were prepared through cyclization of 2'-hydroxychalcone derivatives, the later obtained by Claisen-Schmidt condensation. Since nitric oxide (NO) represents an important inflammatory mediator, the effects of various flavanones on the NO production in the LPS-induced RAW 264.7 macrophage were assessed in vitro using the Griess test. The most active compounds were flavanone (4G), 2'-carboxy-5,7-dimethoxy-flavanone (4F), 4'-bromo-5,7-dimethoxy-flavanone (4D), and 2'-carboxyflavanone (4J), with IC50 values of 0.603, 0.906, 1.030, and 1.830 µg/mL, respectively. In comparison, pinocembrin achieved an IC50 value of 203.60 µg/mL. Thus, the derivatives synthesized in this work had a higher NO inhibition capacity compared to pinocembrin, demonstrating the importance of pharmacomodulation to improve the biological potential of natural molecules. SARs suggested that the use of a carboxyl-group in the meta-position of the B-ring increases biological activity, whereas compounds carrying halogen substituents in the para-position were less active. The addition of methoxy-groups in the meta-position of the A-ring somewhat decreased the activity. This study successfully identified new bioactive flavanones as promising candidates for the development of new anti-inflammatory agents.

Biosorption of nickel ions Ni2+ by natural and modified Pinus caribaea Morelet sawdust.

The potential of Pinus caribaea Morelet sawdust for the removal of nickel ions (Ni2+) and other metallic trace ions (Co2+, Cr3+, Mn2+) from aqueous solutions was investigated under batch conditions. Several parameters such as size of particles, contact time, pH, initial metal and biomass concentrations, desorption conditions and reusability were evaluated on natural biomass. Biosorption was fast, effective (73%) and biomaterial can be reused after five cycles. To enhance the removal capacity of nickel, pine sawdust was modified by acidic and oxidative treatments. Cellulosic residues from sawdust sequential extraction showed great biosorption capacity (96%). In the presence of a metal mixture, oxidized sawdust had better selectivity for Cr3+ ions than for Ni2+ . Pinus caribaea biomass could be an environmental, inexpensive and renewable material for the depollution of water laden with metallic trace elements.

Porphyrin/Chlorin Derivatives as Promising Molecules for Therapy of Colorectal Cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related death. The demand for new therapeutic approaches has increased attention paid toward therapies with high targeting efficiency, improved selectivity and few side effects. Porphyrins are powerful molecules with exceptional properties and multifunctional uses, and their special affinity to cancer cells makes them the ligands par excellence for anticancer drugs. Porphyrin derivatives are used as the most important photosensitizers (PSs) for photodynamic therapy (PDT), which is a promising approach for anticancer treatment. Nevertheless, the lack of solubility and selectivity of the large majority of these macrocycles led to the development of different photosensitizer complexes. In addition, targeting agents or nanoparticles were used to increase the efficiency of these macrocycles for PDT applications. On the other hand, gold tetrapyrrolic macrocycles alone showed very interesting chemotherapeutic activity without PDT. In this review, we discuss the most important porphyrin derivatives, alone or associated with other drugs, which have been found effective against CRC, as we describe their modifications and developments through substitutions and delivery systems.

Lichen Polyphenolic Compounds for the Eradication of Candida albicans Biofilms.

Lichens, due to their symbiotic nature (association between fungi and algae), constitute a chemical factory of original compounds. Polyphenolic compounds (depsides and depsidones) are the main constituents of lichens and are exclusively biosynthesized by these organisms. A panel of 11 polyphenols was evaluated for their anti-biofilm activity against Candida albicans biofilms on the maturation phase (anti-maturation) (MMIC50) as well as on preformed 24-h-old biofilm (anti-biofilm) (MBIC50) using the XTT assay. Minimum inhibitory concentrations of compounds (MICs) against C. albicans planktonic yeast were also determined using a broth microdilution method. While none of the tested compounds were active against planktonic cells (IC50 > 100 µg/ml), three depsides slowed the biofilm maturation (MMIC50 ≤12.5 µg/ml after 48 h of contact with Candida cells). Evernic acid was able to both slow the maturation and reduce the already formed biofilms with MBIC50 ≤12.5 µg/ml after 48 h of contact with the biofilm. This compound shows a weak toxicity against HeLa cells (22%) at the minimal active concentration and no hemolytic activity at 100 µg/ml. Microscopic observations of evernic acid and optimization of its solubility were performed to further study this compound. This work confirmed the anti-biofilm potential of depsides, especially evernic acid, and allows to establish the structure-activity relationships to better explain the anti-biofilm potential of these compounds.

Synthesis and Properties of BODIPY Appended Tetraphenylethylene Scaffolds as Photoactive Arrays.

Tetraphenylethylene (TPE) and its derivatives exhibit excellent aggregation-induced emission (AIE) properties. The TPE unit is easily accessible, and many functional groups can be introduced in a facile manner to yield effective luminescent materials in both solution and the solid-state. It is because of this, several TPE-based compounds have been developed and applied in many areas, such as OLEDs and chemical sensors. Boron dipyrromethenes (BODIPYs) are a class of pyrrolic fluorophore of great interest with myriad application in both material science and biomedical applications. Through the combination of Pd-catalyzed cross-coupling reactions and traditional dipyrromethene chemistry, we present the syntheses of novel tetra-BODIPY-appended TPE derivatives with different distances between the TPE and BODIPY cores. The TPE-BODIPY arrays 6 and 9 show vastly differing AIE properties in THF/H2O systems, with 9 exhibiting dual-AIE, along with both conjugates being found to produce singlet oxygen (1O2). We presume the synthesized BODIPY-appended TPE scaffolds to be utilized for potential applications in the fields of light-emitting systems and theranostics.

Development of Phenalenone-Triazolium Salt Derivatives for aPDT: Synthesis and Antibacterial Screening.

The increasing number of hospital-acquired infections demand the development of innovative antimicrobial treatments. Antimicrobial photodynamic therapy (aPDT) is a versatile technique which relies on the production of reactive oxygen species (ROS) generated by light-irradiated photosensitizers (PS) in the presence of oxygen (O2). 1H-Phenalen-1-one is a very efficient photosensitizer known for its high singlet oxygen quantum yield and its antimicrobial potential in aPDT when covalently bound to quaternary ammonium groups. Triazolium salts are stable aromatic quaternary ammonium salts that recently appeared as interesting moieties endowed with antimicrobial activities. The coupling between phenalenone and triazolium groups bearing various substituents was realized by copper-catalyzed azide-alkyne cycloaddition followed by alkylation with methyl iodide or 2-(bromomethyl)-1H-phenalen-1-one. As expected, most of the compounds retained the initial singlet oxygen quantum yield, close to unity. Minimum inhibitory concentrations (MIC) of 14 new phenalenone-triazolium salt derivatives and 2 phenalenone-triazole derivatives were determined against 6 bacterial strains (Gram-negatives and Gram-positives species). Most of these PS showed significant photoinactivation activities, the strongest effects being observed against Gram-positive strains with as low as submicromolar MIC values.