Potential Weapon Research Articles

CRISPR-cas heterogeneity and plasmid incompatibility types in relation to virulence determinants of Shigella.

Introduction. Virulence factors (VFs) are the most potent weapon in the molecular armoury of Shigella. In bacteria, the mobile genetic elements (MGEs) are contributors to the evolution of different types of clustered regularly interspaced short palindromic repeats-CRISPR associated genes (CRISPR-cas) variants and plasmid incompatibility types. The present study explored the virulence potential of Shigella in relation to the CRISPR-cas pattern and incompatibility types among the isolates.Hypothesis/Gap Statement. The profile of the CRISPR-cas systems among clinical isolates of Shigella in India has not been reported earlier. Limited knowledge is available on the pattern of plasmid incompatibility groups among clinical isolates Shigella. The bias is always towards studying the genetic elements associated with AMR, but the present study highlights CRISPR-cas and incompatibility types among Shigella in association with virulence.Aim. We aimed to investigate the distribution of virulence factors, CRISPR-cas pattern followed by plasmid incompatibility types among Shigella isolates.Methodology. Between 2012-2017, a total of 187 isolates of Shigella were included in the study. The virulence genes' distribution was carried out. CRISPR-cas profiling followed by analysis of the repeats and spacers was carried out. PCR-based replicon typing was used to determine the incompatibility types. The interplay was statistically determined using STATA.Results. The distribution of virulence genes showed varied pattern with ipaH present in all the isolates followed by ompA (93.6 %), virF (66.8 %), ial and sen (60.4 %), set1A (39.6 %) and set1B (39 %). CRISPR 1, CRISPR 3 and Cas6-Cas5 region were dominantly conserved. Twenty-two types of spacers were identified. The CRISPR3 repeat appeared to have a highly conserved sequence. CRISPR2 being the least common CRISPR type showed a strong association with an array of virulence genes (ial-set1A-set1B-virF) while CRISPR1 being the most dominant showed the least association with virulence genes (sen-virF). The dominant plasmids were found to be belonging to the inc FII group. The incompatibility groups FII, IncIγ, U, FIIS, FIIK, K, A/C, I1alpha was found to be associated with a greater number of virulence genes.Conclusion. The isolates showed increasing diversity in their gene content that contributes to increasing heterogeneity among the isolates, which is a known virulence strategy among pathogens.

El General Francisco Franco’s “The Power of Beliefs”

This study analyzes and shows the elements of Francisco Francos’ various speeches and manner in which he targeted people's beliefs and conduct. His prime targets were the higher education organizations, educators and college students. Franco believed they needed to be indoctrinated in order to eradicate the republican beliefs from the previous Spanish administration. Thus he directed his propaganda towards them. His yearning to reach out to teachers and students was evident in Discurso pronunciado por S.E. El Generalísimo Franco, Jefe del Estado Español con motivo de la inauguración del presente curso escolar y de la Ciudad Universitaria de Madrid. The totalitarian vocabulary of the text comprises a utopian vision of reality and covert techniques of persuasion as well as control that, when combined, provided a potent weapon of manipulation. Taking into account both the era’s historical setting and the current political climate, this critical discourse analysis of the speech selected incorporates Wodak’s historical discourse approach with other approaches to analyze topoi in critical discourse. We see in the findings of this article how the combinations of a charismatic leader and power of speech play an important role in obtaining support of the population, even when it is against their own personal interest and well-being.

Natural Strategies as Potential Weapons against Bacterial Biofilms.

Microbial biofilm is an aggregation of microbial species that are either attached to surfaces or organized into an extracellular matrix. Microbes in the form of biofilms are highly resistant to several antimicrobials compared to planktonic microbial cells. Their resistance developing ability is one of the major root causes of antibiotic resistance in health sectors. Therefore, effective antibiofilm compounds are required to treat biofilm-associated health issues. The awareness of biofilm properties, formation, and resistance mechanisms facilitate researchers to design and develop combating strategies. This review highlights biofilm formation, composition, major stability parameters, resistance mechanisms, pathogenicity, combating strategies, and effective biofilm-controlling compounds. The naturally derived products, particularly plants, have demonstrated significant medicinal properties, producing them a practical approach for controlling biofilm-producing microbes. Despite providing effective antibiofilm activities, the plant-derived antimicrobial compounds may face the limitations of less bioavailability and low concentration of bioactive molecules. The microbes-derived and the phytonanotechnology-based antibiofilm compounds are emerging as an effective approach to inhibit and eliminate the biofilm-producing microbes.

Dendrimer-siRNA Conjugates for Targeted Intracellular Delivery in Glioblastoma Animal Models.

Small interfering RNAs (siRNAs) are potent weapons for gene silencing, with an opportunity to correct defective genes and stop the production of undesirable proteins, with many applications in central nervous system (CNS) disorders. However, successful delivery of siRNAs to the brain parenchyma faces obstacles such as the blood-brain barrier (BBB), brain tissue penetration, and targeting of specific cells. In addition, siRNAs are unstable under physiological conditions and are susceptible to protein binding and enzymatic degradation, necessitating a higher dosage to remain effective. To address these issues and advance siRNA delivery, we report the development of covalently conjugated hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimer-siRNA conjugates, demonstrated with a siRNA against GFP (siGFP) conjugate (D-siGFP) utilizing glutathione-sensitive linkers. This allows for precise nucleic acid loading, protects the payload from premature degradation, delivers the siRNA cargo into cells, and achieves significant GFP knockdown in vitro (∼40%) and in vivo (∼30%). Compared to commercially available delivery systems such as RNAi Max and Lipofectamine, D-siGFP retains the potency of the siRNA in vitro. In addition, the dendrimer-siGFP conjugate significantly enhances the half-life of siRNA in the presence of plasma and endonucleases and maintains the passive targeting ability of PAMAM dendrimers to reactive microglia. When administered intratumorally to orthotopic glioblastoma multiform tumors (GBM) in CX3CR-1GFP mice, D-siGFP localizes in tumor-associated macrophages (TAMs) within the tumor parenchyma, minimizing off-target effects in other cell populations. The facile conjugation strategy for dendrimer-siRNA conjugates presented here offers a promising approach for targeted, systemic intracellular delivery of siRNA, serving as a potential bridge for the clinical translation of RNAi therapies.

UNDERSTANDING THE NEED FOR A BROAD DIFFERENTIAL DIAGNOSIS: A CASE OF PNEUMONIC TULAREMIA

UNDERSTANDING THE NEED FOR A BROAD DIFFERENTIAL DIAGNOSIS: A CASE OF PNEUMONIC TULAREMIA

Fighting Climate Change with Synthetic Biology

Fighting Climate Change with Synthetic Biology

RAAV expressing recombinant neutralizing antibody for the botulinum neurotoxin type A prophylaxis.

Botulinum neurotoxin (BoNT) is one of the most dangerous bacterial toxins and a potential biological weapon component. BoNT mechanism of pathological action is based on inhibiting the release of neurotransmitters from nerve endings. To date, anti-BoNT therapy is reduced to the use of horse hyperimmune serum, which causes many side effects, as well as FDA-approved drug BabyBig which consists of human-derived anti-BoNT antibodies (IgG) for infant botulinum treatment. Therapeutics for botulism treatment based on safer monoclonal antibodies are undergoing clinical trials. In addition, agents have been developed for the specific prevention of botulism, but their effectiveness has not been proved. In this work, we have obtained a recombinant adeno-associated virus (rAAV-B11-Fc) expressing a single-domain antibody fused to the human IgG Fc-fragment (B11-Fc) and specific to botulinum toxin type A (BoNT/A). We have demonstrated that B11-Fc antibody, expressed via rAAV-B11-Fc treatment, can protect animals from lethal doses of botulinum toxin type A, starting from day 3 and at least 120 days after administration. Thus, our results showed that rAAV-B11-Fc can provide long-term expression of B11-Fc-neutralizing antibody in vivo and provide long-term protection against BoNT/A intoxication. Consequently, our study demonstrates the applicability of rAAV expressing protective antibodies for the prevention of intoxication caused by botulinum toxins.

“You are no longer cubs, you are now lions”: examining the constructed masculinities of Islamic State child executioners and their victims

ABSTRACT Integral to its military and state-building activities, the Islamic State (IS) terrorist organisation recruited and mobilised large numbers of children into its ranks. The group’s propaganda publications showcase the commitment and skills of its young male militants, with footage focused on training in weapons handling and hand-to-hand combat. Marketed as a potent weapon against IS’ enemies, a sub-set of propaganda videos foregrounds the role of boys in the ultra-violent executions of hostages. This article presents analysis of 20 official IS propaganda videos released between 1 January 2015 and 31 December 2018, in which 71 boys conducted on-camera executions on behalf of the group. Data presented include the setting and method of killing; the profile and “charge” of the victim; and the boy’s nationality, age group, and “justifications” for their acts. Highly staged, these violent displays frame and constitute the status of the young IS “cub” and the adult male hostage as symbols of their respective societies, values, and masculinities. The author examines the juxtaposition of the two figures and their constructed positions in IS’ ideological, military, and masculine hierarchy.

Safety of COVID-19 Vaccines: Spotlight on Neurological Complications.

The COVID-19 pandemic has led to unprecedented demand on the global healthcare system. Remarkably, at the end of 2021, COVID-19 vaccines received approvals for human use in several countries worldwide. Since then, a solid base for response in the fight against the virus has been placed. COVID-19 vaccines have been shown to be safe and effective drugs. Nevertheless, all kinds of vaccines may be associated with the possible appearance of neurological complications, and COVID-19 vaccines are not free from neurological side effects. Neurological complications of COVID-19 vaccination are usually mild, short-duration, and self-limiting. However, severe and unexpected post-vaccination complications are rare but possible events. They include the Guillain-Barré syndrome, facial palsy, other neuropathies, encephalitis, meningitis, myelitis, autoimmune disorders, and cerebrovascular events. The fear of severe or fatal neurological complications fed the “vaccine hesitancy” phenomenon, posing a vital communication challenge between the scientific community and public opinion. This review aims to collect and discuss the frequency, management, and outcome of reported neurological complications of COVID-19 vaccines after eighteen months of the World Health Organization’s approval of COVID-19 vaccination, providing an overview of safety and concerns related to the most potent weapon against the SARS-CoV-2.

Aminopeptidase N Inhibitors as Pointers for Overcoming Antitumor Treatment Resistance.

Aminopeptidase N (APN), also known as CD13 antigen or membrane alanyl aminopeptidase, belongs to the M1 family of the MA clan of zinc metallopeptidases. In cancer cells, the inhibition of aminopeptidases including APN causes the phenomenon termed the amino acid deprivation response (AADR), a stress response characterized by the upregulation of amino acid transporters and synthetic enzymes and activation of stress-related pathways such as nuclear factor kB (NFkB) and other pro-apoptotic regulators, which leads to cancer cell death by apoptosis. Recently, APN inhibition has been shown to augment DR4-induced tumor cell death and thus overcome resistance to cancer treatment with DR4-ligand TRAIL, which is available as a recombinant soluble form dulanermin. This implies that APN inhibitors could serve as potential weapons for overcoming cancer treatment resistance. In this study, a series of basically substituted acetamidophenones and the semicarbazones and thiosemicarbazones derived from them were prepared, for which APN inhibitory activity was determined. In addition, a selective anti-proliferative activity against cancer cells expressing APN was demonstrated. Our semicarbazones and thiosemicarbazones are the first compounds of these structural types of Schiff bases that were reported to inhibit not only a zinc-dependent aminopeptidase of the M1 family but also a metalloenzyme.

Plague, Pestilence and the Peninsula: International Humanitarian Law Concerns of North Korea’s Biological Weapons Program

Abstract Suspected development of advanced biological weapons by the Democratic People’s Republic of Korea (North Korea), despite its status as a party to both the Biological Weapons Convention and other nonproliferation agreements, bears significant implications for both public health and security around the globe. A steady decrease in resources and attention devoted to preparedness for biological attacks or outbreaks since 2001 has exacerbated the vulnerability of the USA and its allies to outbreaks of such pathogens, both from North Korean biological weapons and natural sources. This article assesses several International Humanitarian Law (IHL) issues raised by the prospect of an international armed conflict in which North Korea deploys biological weapons. Historical context is discussed to contextualize the various IHL issues raised by a potential armed conflict, which include United Nations Enforcement actions, anticipatory self-defense, protection of civilians, targeting and proportionality. Preparing for and responding to a potential biological weapons attack by North Korea presents a host of unique challenges for the USA and its allies. An international armed conflict involving the use of such weapons by North Korea against the USA or its allies would be devastating for civilians and military personnel alike. It is thus imperative to understand the IHL issues raised by such a conflict, including circumstances that would warrant pre-emptive use of force by the USA and its allies, the scale and scope of any military response, and the need to protect civilians throughout the Korean peninsula.

Artificial Intelligence: As an innovative technique in healthcare sector and as a potent technique to fight against COVID-19

Artificial Intelligence (AI) is refers to an innovative technique which generally deals with the machines. AI re use do decrease or minimize the errors and defects in any field. It is a widely separated technique which is used in many fields and especially in pharama sector it is growing day by day to set the new goals and achieved the new and difficult tasks. AI is also used in the detection, diagnosis, prevention and treatment of covid-19. In the crises of covid- 19 or pandemic of covid the AI technology is used as a very potent and powerful weapon. The AI technology needs some work & time to make and innovative and bright future in health care sector. This article provides a brief overview about the technique of AI it’s applications, use of AI technique as a potent weapon in covid pandemic problems associated with AI and last but not the least feature of AI in healthcare. Keywords: Artificial Intelligence, History, Applications of AI, Advantages & Disadvantages, AI in COVID Pandemic, Litrature review, problems associated with AI

Hybrid Threats – Means of Destabilization of Law and Order in Modern Democratics Societes. Idea and Methodology of Proposed Research

Threats are one of the most serious threats to the legal order of a democratic state. Their non-linear, asymmetric nature makes them more dangerous than other threats to the legal order. The use of multifaceted measures as a weapon disrupts, above all, the legal order of the state. Hybrid threats rely heavily on non-military domains. Civilian populations are central to the hybrid threat scenarios as sources for potential socio-political vulnerabilities and as targets for non-military threats and attacks, not least disinformation campaigns. A significant part of the hybrid threat phenomena is psychological. Actors targeting communities/societies to exacerbate weaknesses do not necessarily create social vulnerabilities themselves but make use of divisions that already exist in civil society. Using disinformation, populations are targeted and used as potential weapons within the state/society in question. This paper shows a concrete scientific approach to the study to of this issue.

“Biafrans Are Not Nazis:” The Biafran Humanitarian Disaster and Trudeau’s Analogies

During the Nigeria-Biafra War, the Nigerian government employed shooting and economic blockade as powerful instruments of uniting the country and defending its territorial integrity. Starvation as a potent weapon was of a magnitude that arguably made it the worst catastrophe since the Second World War. The tension was between sovereignty and human rights. Public opinion in Canada strongly favored humanitarian support for Biafra, but the Canadian government argued that humanitarian aid for Biafra might be offensive to the Nigerian government. This article examines the attitude of Pierre Trudeau to the Biafran humanitarian crisis. It argues that Trudeau’s analogical arguments did not represent the true situation of the war. Although Trudeau’s reliance on information from the Commonwealth secretariat affected his understanding of the crisis, his policies were largely influenced by domestic political issues, particularly the Quebec separatist movement. The paper concludes that Canada’s foreign policy reviews that coincided with the Nigeria–Biafra War informed Trudeau’s kneejerk response to the Biafran humanitarian crisis.

Secondary Ammonium-Based Hyperbranched Poly(amidoamine) with Excellent Membrane-Active Property for Multidrug-Resistant Bacterial Infection.

With the rapid emergence of microbial infections induced by "superbugs", public health and the global economy are threatened by the lack of effective and biocompatible antibacterial agents. Herein, we systematically design a series of secondary ammonium-based hyperbranched poly(amidoamine) (SAHBP) with different alkyl chain lengths for probing high-efficacy antibacterial agents. SAHBP modified with alkyl tails at the hyperbranched core could efficiently kill Escherichia coli and Staphylococcus aureus, two types of clinically important bacteria worldwide. The best SAHBP with 12-carbon-long alkyl tails (SAHBP-12) also showed high activity against problematic multidrug-resistant bacteria, including Pseudomonas aeruginosa and methicillin-resistant S. aureus (MRSA). Based on ζ potential, isothermal titration microcalorimetry (ITC), and membrane integrity assays, it is found that SAHBP-12 could attach to the cell membrane via electrostatic adsorption and hydrophobic interactions, following which the integrity of the bacterial cell wall and the cell membrane is disrupted, resulting in severe cell membrane damage and the leakage of cytoplasmic contents, finally causing bacterial cell death. Impressively, benefiting from excellent membrane-active property, SAHBP-12 exhibited robust therapeutic efficacy in MRSA-infected mice wounds. Moreover, SAHBP-12 also showed excellent biosafety in vitro and in vivo, which undoubtedly distinguished it as a potent weapon in combating the growing threat of problematic multidrug-resistant bacterial infections.

To kill or to be killed: pangenome analysis of Escherichia coli strains reveals a tailocin specific for pandemic ST131

BackgroundEscherichia coli (E. coli) has been one of the most studied model organisms in the history of life sciences. Initially thought just to be commensal bacteria, E. coli has shown wide phenotypic diversity including pathogenic isolates with great relevance to public health. Though pangenome analysis has been attempted several times, there is no systematic functional characterization of the E. coli subgroups according to the gene profile.ResultsSystematically scanning for optimal parametrization, we have built the E. coli pangenome from 1324 complete genomes. The pangenome size is estimated to be ~25,000 gene families (GFs). Whereas the core genome diminishes as more genomes are added, the softcore genome (≥95% of strains) is stable with ~3000 GFs regardless of the total number of genomes. Apparently, the softcore genome (with a 92% or 95% generation threshold) can define the genome of a bacterial species listing the critically relevant, evolutionarily most conserved or important classes of GFs. Unsupervised clustering of common E. coli sequence types using the presence/absence GF matrix reveals distinct characteristics of E. coli phylogroups B1, B2, and E. We highlight the bi-lineage nature of B1, the variation of the secretion and of the iron acquisition systems in ST11 (E), and the incorporation of a highly conserved prophage into the genome of ST131 (B2). The tail structure of the prophage is evolutionarily related to R2-pyocin (a tailocin) from Pseudomonas aeruginosa PAO1. We hypothesize that this molecular machinery is highly likely to play an important role in protecting its own colonies; thus, contributing towards the rapid rise of pandemic E. coli ST131.ConclusionsThis study has explored the optimized pangenome development in E. coli. We provide complete GF lists and the pangenome matrix as supplementary data for further studies. We identified biological characteristics of different E. coli subtypes, specifically for phylogroups B1, B2, and E. We found an operon-like genome region coding for a tailocin specific for ST131 strains. The latter is a potential killer weapon providing pandemic E. coli ST131 with an advantage in inter-bacterial competition and, suggestively, explains their dominance as human pathogen among E. coli strains.

Analysis of the Virus SARS-CoV-2 as a Potential Bioweapon in Light of International Literature.

ABSTRACTIntroductionAs of early 2022, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic still represents a worldwide medical emergency situation. The ongoing vaccination programs can slow down the spread of the virus; however, from time to time, the newly emerging variants of concern and antivaccination movements carry the possibility for the disease to remain in our daily lives. After the appearance of SARS-CoV-2, there was scholarly debate whether the virus was of natural origin, or it emerged from a laboratory, some even thinking the agent’s potential biological weapon properties suggest the latter scenario. Later, the bioweapon theory was dismissed by the majority of experts, but the question remains that despite its natural origin, how potent a biological weapon the SARS-CoV-2 virus can become over time.Materials and MethodsBased on 12 bioweapon threat assessment criteria already published in 2018, we performed a literature search and review, focusing on relevant potential bioweapon properties of the virus SARS-CoV-2. Instead of utilizing a survey among experts, we tried to qualify and quantify characteristics according to the available data found in peer-reviewed papers. We also identified other key elements not mentioned in the original 12 bioweapon criteria, which can play an important role in assessing future biological weapons.ResultsAccording to the international literature we analyzed, SARS-CoV-2 is a moderately infectious agent (ID50 estimated between 100 and 1,000), with high infection-to-disease ratio (35%–45% rate of asymptomatic infected) and medium incubation period (1–34 days, mean 6–7 days). Its morbidity and mortality rate can be categorized as medium (high morbidity rate with significant mortality rate). It can be easily produced in large quantities, has high aerosol stability, and has moderate environmental stability. Based on laboratory experiments and statistical model analysis, it can form and is contagious with droplet nuclei, and with spray technique utilization, it could be weaponized effectively. Several prophylactic countermeasures are available in the form of vaccines; however, specific therapeutic options are much more limited. In connection with the original assessment criteria, the SARS-CoV-2 only achieved a “0” score on the ease of detection because of readily available, relatively sensitive, and specific rapid antigen tests. Based on the pandemic experience, we also propose three new assessment categories: one that establishes a mean to measure the necessary quarantine restrictions related to a biological agent, another one that can represent the personal protective equipment required to work safely with a particular agent, and a third one that quantifies the overall disruptive capability, based on previous real-life experiences. These factors could further specify the threat level related to potential biological weapons.ConclusionsOur results show that the virus can become a potent bioweapon candidate in the future, achieving a total score of 24 out of 36 on the original 12 criteria. The SARS-CoV-2 has already proven its pandemic generating potential and, despite worldwide efforts, still remains an imminent threat. In order to be prepared for the future possibility of the virus arising as a bioweapon, we must remain cautious and take the necessary countermeasures.

Metabolic Effects of Sodium Fluorocitrate and Potential Treatments on Saccharomyces Cerevisiae: Changes in Oxygen Consumption

Sodium fluoroacetate (1080) is a colorless, odorless, tasteless, water‐soluble metabolic poison. In the body, fluoroacetate is converted to fluorocitrate (FC) which blocks the citric acid cycle and drastically decreases ATP production. Symptoms of exposure include nausea, vomiting, abdominal pains, salivation, irrational fear, weakness, tachypnea, cyanosis, sweating, increased temperature, and death. Signs and symptoms of 1080 poisoning are nonspecific, further complicating the diagnosis. 1080 is tightly regulated within the United States, but it is commonly used in Australia, New Zealand, Mexico, Japan, South Korea, and Israel as a rodenticide to control invasive and predatory species. An eco‐terrorist scare in New Zealand (2015) and findings reported by the CIA (2007) have led 1080 to being identified as a potential terrorist weapon.To identify potential countermeasures against 1080 poisoning, a Saccharomyces cerevisiae (yeast) model was selected to assess the impact of FC on cellular respiration and to screen candidate therapeutics. In response to FC, yeast showed depressed mitochondrial activity as measured by oxygen consumption rate (OCR). Potential treatments, thonzonium bromide, nifuroxazide, pyrvinium pamoate, menadione, mefloquine, clemastine fumarate, bisacodyl, L‐ascorbic acid, thiethylperazine and vinpocitine, were examined in this study. All treatments are approved by the Food and Drug Administration. Toxicity of each treatment was also assessed.Assays were performed in yeast extract peptone galactose media, a metabolically restrictive media. To assess the effect of FC on OCR, cells were exposed to 50 µM, 100 µM, and 200 µM FC in liquid culture for 1, 4, or 24 hours. After incubation, mitochondrial respiration was assessed via the MitoXpress assay (Agilent), a fluorescence‐based assay that measures OCR. Once established as a viable model, yeasts were then used to screen therapeutics to improve cellular respiration. Yeast was co‐incubated with fluorocitrate (200 µM), and potential treatments at three increasing concentrations for 4 hours and the effects on mitochondrial respiration were assessed via the MitoXpress assay.Following the decreased OCR in yeast exposed to FC, 6 of the 10 treatments successfully restored the mitochondrial function of yeast as demonstrated by an increase in OCR. As a result, the compounds nifuroxazide, pyrvinium pamoate, vinpocitine, clemastine fumarate, bisacodyl, and L‐ascorbic acid are moving forward for further testing in cardiomyocytes and hepatic spheroids, with potential in vivo assessment, to characterize their effectiveness against 1080 poisoning. Future studies will continue to use yeast as a valuable screening method to identify other potential treatments for sodium fluoroacetate.

Potent and Broad-Spectrum Bactericidal Activity of a Nanotechnologically Manipulated Novel Pyrazole.

The antimicrobial potency of the pyrazole nucleus is widely reported these days, and pyrazole derivatives represent excellent candidates for meeting the worldwide need for new antimicrobial compounds against multidrug-resistant (MDR) bacteria. Consequently, 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), recently reported as a weak antiproliferative agent, was considered to this end. To overcome the CR232 water solubility issue and allow for the determination of reliable minimum inhibitory concentration values (MICs), we initially prepared water-soluble and clinically applicable CR232-loaded nanoparticles (CR232-G5K NPs), as previously reported. Here, CR232-G5K NPs have been tested on several clinically isolates of Gram-positive and Gram-negative species, including MDR strains. While for CR232 MICs ≥ 128 µg/mL (376.8 µM) were obtained, very low MICs (0.36–2.89 µM) were observed for CR232-G5K NPs against all of the considered isolates, including colistin-resistant isolates of MDR Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemases (KPCs)-producing K. pneumoniae (0.72 µM). Additionally, in time–kill experiments, CR232-G5K NPs displayed a rapid bactericidal activity with no significant regrowth after 24 h on all isolates tested, regardless of their difficult-to-treat resistance. Conjecturing a clinical use of CR232-G5K NPs, cytotoxicity experiments on human keratinocytes were performed, determining very favorable selectivity indices. Collectively, due to its physicochemical and biological properties, CR232-G5K NPs could represent a new potent weapon to treat infections sustained by broad spectrum MDR bacteria.

Lactic acid bacteria and their bacteriocins: new potential weapons in the fight against methicillin-resistant Staphylococcus aureus.

Alternative solutions are eminently needed to combat the escalating number of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Bacteriocins produced by lactic acid bacteria are promising candidates for next-generation antibiotics. Studies have found that these stable and nontoxic ribosomally synthesized antimicrobial peptides exhibit significant potency against other bacteria, including antibiotic-resistant strains. Herethe authors review previous studies on bacteriocins that have been effectively employed to manage MRSA infections. The authors' review focuses on the beneficial traits of bacteriocins for further application as templates for the design of novel drugs. Treatments that combine bacteriocins with other antimicrobials to combat pervasive MRSA infections are also highlighted. In short, future studies should focus on the pharmacodynamics and pharmacokinetics of bacteriocins-antimicrobials to understand their interactions, as this aspect would likely determine their efficacy in MRSA inhibition.