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Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials. ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete. ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (−1·5% [95% CI −10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI −0·3 to 20·4]). Safety profiles were similar across groups. Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis. Melinta Therapeutics and Cidara Therapeutics.

The lipopeptides of Bacillus are small metabolites that contain a cyclic structure formed by 7–10 amino acids (including 2–4 d -amino acids) and a beta-hydroxy fatty acid with 13–19 C atoms. These lipopeptides exhibit a variety of biological activities, including interactions with biofilms, and anti-fungal, anti-inflammatory, anti-tumor, anti-virus, and anti-platelet properties. The multiple activities of lipopeptides have stimulated significant interest in the exploitation of these lipopeptides for use as antibiotics, feed additives, anti-tumor agents, urgent thrombolytic therapeutic agents, and drug delivery systems. Understanding the natural function of these structurally diverse lipopeptides in Bacillus provides insight into microbial regulatory programs and is required for efficient development of more effective products. Currently, there is still insufficient knowledge of the direct target of these lipopeptides, and continued efforts are needed to enhance their biosynthesis efficiency for industrial applications.

Probiotic nutrition is frequently claimed to improve human health. In particular, live probiotic bacteria obtained with food are thought to reduce intestinal colonization by pathogens, and thus to reduce susceptibility to infection. However, the mechanisms that underlie these effects remain poorly understood. Here we report that the consumption of probiotic Bacillus bacteria comprehensively abolished colonization by the dangerous pathogen Staphylococcus aureus in a rural Thai population. We show that a widespread class of Bacillus lipopeptides, the fengycins, eliminates S . aureus by inhibiting S . aureus quorum sensing—a process through which bacteria respond to their population density by altering gene regulation. Our study presents a detailed molecular mechanism that underlines the importance of probiotic nutrition in reducing infectious disease. We also provide evidence that supports the biological significance of probiotic bacterial interference in humans, and show that such interference can be achieved by blocking a pathogen’s signalling system. Furthermore, our findings suggest a probiotic-based method for S . aureus decolonization and new ways to fight S . aureus infections. Lipopeptides secreted by Bacillus bacteria block quorum sensing by Staphylococcus aureus and thereby inhibit the growth of this opportunistic pathogen in the gut, suggesting why people in rural Thailand who are colonized by Bacillus are not also colonized by S . aureus .

The escalating interest in Bacillus velezensis as a biocontrol agent arises from its demonstrated efficacy in inhibiting both phytopathogenic fungi and bacteria, positioning it as a promising candidate for biotechnological applications. This mini review aims to offer a comprehensive exploration of the multifaceted properties of B. velezensis , with particular focus on its beneficial interactions with plants and its potential for controlling phytopathogenic fungi. The molecular dialogues involving B. velezensis , plants, and phytopathogens are scrutinized to underscore the intricate mechanisms orchestrating these interactions. Additionally, the review elucidates the mode of action of B. velezensis , particularly through cyclic lipopeptides, highlighting their importance in biocontrol and promoting plant growth. The agricultural applications of B. velezensis are detailed, showcasing its role in enhancing crop health and productivity while reducing reliance on chemical pesticides. Furthermore, the review extends its purview in the industrial and environmental arenas, highlighting its versatility across various sectors. By addressing challenges such as formulation optimization and regulatory frameworks, the review aims to chart a course for the effective utilization of B. velezensis . Key points • B. velezensis fights phytopathogens, boosting biotech potential • B. velezensis shapes agri-biotech future, offers sustainable solutions • Explores plant-B. velezensis dialogue, lipopeptide potential showcased

Ultrashort cationic lipopeptides (USCLs) are considered to be a promising class of antimicrobials with high activity against a broad-spectrum of microorganisms. However, the majority of these compounds are characterized by significant toxicity toward human cells, which hinders their potential application. To overcome those limitations, several approaches have been advanced. One of these is disulfide cyclization that has been shown to improve drug-like characteristics of peptides. In this article the effect of disulfide cyclization of the polar head of N-palmitoylated USCLs on in vitro biological activity has been studied. Lipopeptides used in this study consisted of three or four basic amino acids (lysine and arginine) and cystine in a cyclic peptide. In general, disulfide cyclization of the lipopeptides resulted in peptides with reduced cytotoxicity. Disulfide-cyclized USCLs exhibited improved selectivity between Candida sp., Gram-positive strains and normal cells in contrast to their linear counterparts. Interactions between selected USCLs and membranes were studied by molecular dynamics simulations using a coarse-grained force field. Moreover, membrane permeabilization properties and kinetics were examined. Fluorescence and transmission electron microscopy revealed damage to Candida cell membrane and organelles. Concluding, USCLs are strong membrane disruptors and disulfide cyclization of polar head can have a beneficial effect on its in vitro selectivity between Candida sp. and normal human cells.

Main conclusion Lipopeptides could help to overcome a large concern in agriculture: resistance against chemical pesticides. These molecules have activity against various phytopathogens and a potential to be transformed by genetic engineering. The exponential rise of pest resistances to different chemical pesticides and the global appeal of consumers for a sustainable agriculture and healthy nutrition have led to the search of new solutions for pest control. Furthermore, new laws require a different stance of producers. Based on that, bacteria of the genus Bacillus present a great agricultural potential, producing lipopeptides (LPs) that have high activity against insects, mites, nematodes, and/or phytopathogens that are harmful to plant cultures. Biopesticide activity can be found mainly in three families of Bacillus lipopeptides: surfactin, iturin, and fengycin. These molecules have an amphiphilic nature, interfering with biological membrane structures. Their antimicrobial properties include activity against bacteria, fungi, oomycetes, and viruses. Recent studies also highlight the ability of these compounds to stimulate defense mechanisms of plants and biofilm formation, which is a key factor for the successful colonization of biocontrol organisms. The use of molecular biology has also recently been researched for continuous advances and discoveries of new LPs, avoiding possible future problems of resistance against these molecules. As a consequence of the properties and possibilities of LPs, numerous studies and developments as well as the attention of large companies in the field is expected in the near future.

In 1968, Arima et al. discovered the heptapeptide, known as surfactin, which belongs to a family of lipopeptides. Known for its ability to reduce surface tension, it also has biological activities such as antimicrobial and antiviral. Its non-ribosomal synthesis mechanism was later discovered (1991). Lipopeptides represent an important class of surfactants, which can be applied in many industrial sectors such as food, pharmaceutical, agrochemicals, detergents, and cleaning products. Currently, 75% of the surfactants used in the various industrial sectors are from the petrochemical industry. Nevertheless, there are global current demands (green chemistry concept) to replace the petrochemical products with environmentally friendly products, such as surfactants by biosurfactants. The production biosurfactants still are costly. Thus, an alternative to reduce the production costs is using agro-industrial waste as a culture medium associated with an efficient and scalable purification process. This review puts a light on the agro-industrial residues used to produce surfactin and the techniques used for its recovery.

Background. Invasive fungal infection (IFI) following liver transplant is associated with significant morbidity and mortality. Antifungal prophylaxis is rational for liver transplant patients at high IFI risk. Methods. In this open-label, noninferiority study, patients were randomized 1:1 to receive intravenous micafungin 100 mg or center-specific standard care (fluconazole, liposomal amphotericin B, or caspofungin) posttransplant. The primary endpoint was clinical success (absence of a proven/probable IFI and no need for additional antifungals) at end of prophylaxis (EOP). Noninferiority (10% margin) of micafungin vs standard care was assessed in the per protocol and full analysis sets. Safety assessments included adverse events and liver and kidney function tests. Results. The full analysis set comprised 344 patients (172 micafungin; 172 standard care). Mean age was 51.2 years; 48.0% had a Model for End-Stage Liver Disease score ≥20. At EOP (mean treatment duration, 17 days), clinical success was 98.6% for micafungin and 99.3% for standard care (Δ standard care – micafungin [95% confidence interval], 0.7% [−2.7% to 4.4%]) in the per protocol set and 96.5% and 93.6%, respectively (−2.9% [−8.0% to 1.9%]), in the full analysis set. Incidences of drug-related adverse events for micafungin and standard care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively. At EOP, liver function tests were similar but creatinine clearance was higher in micafungin- vs standard care–treated patients. Conclusions. Micafungin was noninferior to standard care as antifungal prophylaxis in liver transplant patients at high risk for IFI. Adverse event profiles and liver function at EOP were similar, although kidney function was better with micafungin. Clinical Trials Registration. NCT01058174.

The synthetic bioinformatic natural products (syn-BNPs) approach identifies putative natural products that are validated directly by independent synthesis. Its application led to the identification of humimycins, non-ribosomal peptides that have antimicrobial activity in mice. Here we present a natural product discovery approach, whereby structures are bioinformatically predicted from primary sequence and produced by chemical synthesis (synthetic-bioinformatic natural products, syn-BNPs), circumventing the need for bacterial culture and gene expression. When we applied the approach to nonribosomal peptide synthetase gene clusters from human-associated bacteria, we identified the humimycins. These antibiotics inhibit lipid II flippase and potentiate β-lactam activity against methicillin-resistant Staphylococcus aureus in mice, potentially providing a new treatment regimen.

Bacillus cyclic lipopeptides (CLP), part of the three main families—surfactins, iturins, and fengycins—are secondary metabolites with a unique chemical structure that includes both peptide and lipid components. Being amphiphilic compounds, CLPs exhibit antimicrobial activity in vitro, damaging the membranes of microorganisms. However, the concentrations of CLPs used in vitro are difficult to achieve in natural conditions. Therefore, in a natural environment, alternative mechanisms of antimicrobial action by CLPs are more likely, such as inducing apoptosis in fungal cells, preventing microbial adhesion to the substrate, and promoting the death of phytopathogens by stimulating plant immune responses. In addition, CLPs in low concentrations act as signaling molecules of Bacillus’s own metabolism, and when environmental conditions change, they form an adaptive response of the host bacterium. Namely, they trigger the differentiation of the bacterial population into various specialized cell types: competent cells, flagellated cells, matrix producers, and spores. In this review, we have summarized the current understanding of the antimicrobial action of Bacillus CLPs under both experimental and natural conditions. We have also shown the relationship between some regulatory pathways involved in CLP biosynthesis and bacterial cell differentiation, as well as the role of CLPs as signaling molecules that determine changes in the physiological state of Bacillus subpopulations in response to shifts in environmental conditions.