Effective Treatment Of Infectious Diseases Research Articles

In Vitro Antibacterial Activity of Microbial Natural Products against Bacterial Pathogens of Veterinary and Zoonotic Relevance.

Antimicrobial resistance (AMR) is considered one of the greatest threats to both human and animal health. Efforts to address AMR include implementing antimicrobial stewardship programs and introducing alternative treatment options. Nevertheless, effective treatment of infectious diseases caused by bacteria will still require the identification and development of new antimicrobial agents. Eight different natural products were tested for antimicrobial activity against seven pathogenic bacterial species (Brachyspira sp., Chlamydia sp., Clostridioides sp., Mannheimia sp., Mycobacterium sp., Mycoplasma sp., Pasteurella sp.). In a first pre-screening, most compounds (five out of eight) inhibited bacterial growth only at high concentrations, but three natural products (celastramycin A [CA], closthioamide [CT], maduranic acid [MA]) displayed activity at concentrations <2 µg/mL against Pasteurella sp. and two of them (CA and CT) also against Mannheimia sp. Those results were confirmed by testing a larger collection of isolates encompassing 64 Pasteurella and 56 Mannheimia field isolates originating from pigs or cattle, which yielded MIC90 values of 0.5, 0.5, and 2 µg/mL against Pasteurella and 0.5, 4, and >16 µg/mL against Mannheimia for CA, CT, and MA, respectively. CA, CT, and MA exhibited higher MIC50 and MIC90 values against Pasteurella isolates with a known AMR phenotype against commonly used therapeutic antimicrobial agents than against isolates with unknown AMR profiles. This study demonstrates the importance of whole-cell antibacterial screening of natural products to identify promising scaffolds with broad- or narrow-spectrum antimicrobial activity against important Gram-negative veterinary pathogens with zoonotic potential.

FARPA-based tube array coupled with quick DNA extraction enables ultra-fast bedside detection of antibiotic-resistant pathogens.

Rapid and accurate detection of pathogens and antimicrobial-resistant (AMR) genes of the pathogens are crucial for the clinical diagnosis and effective treatment of infectious diseases. However, the time-consuming steps of conventional culture-based methods inhibit the precise and early application of anti-infection therapy. For the prompt treatment of pathogen-infected patients, we have proposed a novel tube array strategy based on our previously reported FARPA (FEN1-aided recombinase polymerase amplification) principle for the ultra-fast detection of antibiotic-resistant pathogens on site. The entire process from "sample to result" can be completed in 25 min by combining quick DNA extraction from a urine sample with FARPA to avoid the usually complicated DNA extraction step. Furthermore, a 36-tube array made from commercial 384-well titre plates was efficiently introduced to perform FARPA in a portable analyser, achieving an increase in the loading sample throughput (from several to several tens), which is quite suitable for the point-of-care testing (POCT) of multiple pathogens and multiple samples. Finally, we tested 92 urine samples to verify the performance of our proposed method. The sensitivities for the detection of E. coli, K. pneumoniae, E. faecium, and E. faecalis were 92.7%, 93.8%, 100% and 88.9%, respectively. The specificities for the detection of the four pathogens were 100%. Consequently, our rapid, low-cost and user-friendly POCT method holds great potential for guiding the rational use of antibiotics and reducing bacterial resistance.

The Problem of Antibiotic Resistance Control: A Possible Alternative to Antimicrobials in Veterinary Medicine

Aim of Study: The study included prospects for using autogenous immunobiological drugs as an alternative to antimicrobials. Materials and Methods: For the analysis databases of WHO–World Health Organization, WOHA–World Organization for Animal Health, FAO–Food and Agricultural Organization, CDC–Center for Control and of disease prevention in the USA, ECDC– European Center for Disease Control and Prevention, EFSA–European Food Safety Authority, as well as informational Internet resources of scientific journals, normative legal acts of Ukraine. The Results: According to the results of the conducted analysis, the global spread of microorganisms resistant to the action of antimicrobial drugs was established, which jeopardizes the possibility of effective treatment of infectious diseases. In Ukraine, as in other developed countries of the world, strict regulation of the circulation of antimicrobials has been adopted at the legislative level, which inevitably leads to the limitation of their use. International experience shows that restrictions on the use of antimicrobial agents should be compensated by measures aimed at increasing the level of biosafety. The use of autogenous immunobiological drugs for the specific prevention of infectious diseases of bacterial etiology can be a reasonable alternative to antibiotics in veterinary medicine. Conclusions: The introduction of new rules for the circulation of veterinary antimicrobial drugs will significantly affect the level of use of antimicrobial drugs. A reasonable alternative to antimicrobial agents is the use of autogenous immunobiological agents.

Antibiofilm Activity of Azadirachta indica and Catharanthus roseus and Their Synergistic Effects in Combination with Antimicrobial Agents against Fluconazole-Resistant Candida albicans Strains and MRSA

The rapid emergence and spread of antimicrobial resistance has become a global public health concern that threatens the effective treatment of infectious diseases. One major approach adopted to overcome antimicrobial resistance is the use of plant extracts individually and/or with combination of antibiotics with plant extracts, which may lead to new ways of treating infectious diseases and essentially representing a potential area for further future investigations. In this study, the antifungal activities of Azadirachta indica leaf and Catharanthus roseus flower extracts against fluconazole-resistant Candida albicans strains (isolated from pregnant women with vulvovaginal candidiasis) and anti-methicillin-resistant Staphylococcus aureus (MRSA) were evaluated by agar well diffusion, microdilution, and biofilm inhibition assays. Subsequently, the determination of the combined antimicrobial activity of the individual plant extracts with (fluconazole and voriconazole) and (ampicillin, tetracycline, and streptomycin) against C. albicans strains and MRSA, respectively, was evaluated by checkerboard microdilution assay. Results from the study showed that the antimicrobial activity of the two plant extracts determined by time-kill kinetics was fungistatic with their MICs ranging from 0.1 to 4 mg/mL. Interestingly, all extracts were proved as good biofilm inhibitors of resistant C. albicans and MRSA from 10.1 to 98.82%. Their combination interaction with fluconazole, voriconazole, ampicillin, tetracycline, and streptomycin ranged from synergy to antagonism as per the parameters used. Overall, these results showed that A. indica leaf and C. roseus flower extracts have significant antifungal property. Furthermore, A. indica leaf and C. roseus flower extracts alone or in combination with fluconazole and voriconazole could provide a promising approach to the management of candidiasis caused by drug-resistant strains as well as their interaction with the antibacterial agents to combat the common infections caused by MRSA.

Artificial intelligence and machine learning assisted drug delivery for effective treatment of infectious diseases.

In the era of antimicrobial resistance, the prevalence of multidrug-resistant microorganisms that resist conventional antibiotic treatment has steadily increased. Thus, it is now unquestionable that infectious diseases are significant global burdens that urgently require innovative treatment strategies. Emerging studies have demonstrated that artificial intelligence (AI) can transform drug delivery to promote effective treatment of infectious diseases. In this review, we propose to evaluate the significance, essential principles, and popular tools of AI in drug delivery for infectious disease treatment. Specifically, we will focus on the achievements and key findings of current research, as well as the applications of AI on drug delivery throughout the whole antimicrobial treatment process, with an emphasis on drug development, treatment regimen optimization, drug delivery system and administration route design, and drug delivery outcome prediction. To that end, the challenges of AI in drug delivery for infectious disease treatments and their current solutions and future perspective will be presented and discussed.

Antimicrobial resistance awareness and antibiotic prescribing behavior among healthcare workers in Nigeria: a national survey

BackgroundAntimicrobial resistance (AMR) is a global problem compromising the effective treatment of infectious diseases. The World Health Organization (WHO) is encouraging and promoting awareness creation among health workers as one of its strategies to reduce the rate of emergence and transmission of AMR. Available data on the prescribing behavior of healthcare workers (HCWs) in Nigeria remains incomplete. This study was designed to provide an up-to-date estimate of the knowledge, attitude and antibiotic prescribing behavior of HCWs in Nigeria.MethodsThis is a cross-sectional study. Self-administered questionnaires were distributed to healthcare workers selected from six states, one each from the 6 geopolitical zones in Nigeria. A multi-stage sampling technique was used to reflect the three tiers of healthcare: primary, secondary and tertiary levels. Quantitative data was summarized using descriptive statistics. All data analysis was done using the Statistical package for social sciences version 26.0.ResultsOf the 420 questionnaires distributed, 358 (85.2%) responded. The mean year of practice of the respondents was 9.32 ± 7.8 years. About a half (50.3%) agreed that their prescribing behavior could promote antimicrobial resistance. 49.2% had a good knowledge of AMR and physicians had significantly better knowledge than other HCWs (X2 = 69.59, P < 0.001). Several participants prescribed antibiotics for common viral infections such as sore throats (75.7%), measles (37.7%), common cold and flu (21.2%). Over 60.3% admitted prescribing antibiotics just to be on the safe side. In general, 70.9% of the respondents frequently or moderately use practice guidelines while 25.7% often apply the delayed antibiotic prescription (DAP) strategy to reduce antimicrobial prescription.ConclusionThis study reveals an overall moderate level of knowledge of AMR and attitude towards minimizing the emergence of antimicrobial resistance though this did not translate significantly to practice. Further efforts must be made in order to improve rational prescription of antimicrobials among HCWs in Nigeria.

Preventing Candida albicans biofilm formation using aromatic-rich piperazines

The global increase in microbial resistance is an imminent threat to public health. Effective treatment of infectious diseases now requires new antimicrobial therapies. We report herein the discovery of aromatic-rich piperazines that inhibit biofilm formation by C. albicans. 22 piperazines, including 16 novel ones, were prepared efficiently using a combination of solid- and solution phase synthesis. The most potent compound prevents morphological switching under several hypha-inducing conditions and reduces C. albicans’ ability to adhere to epithelial cells. These processes are essential to the development of Candida biofilms, which are associated with its increased resistance to immune defenses and antifungal agents.

New EUCAST definitions of S, I and R from 2019 - German physicians are largely not aware of the changes.

On January 1st 2019, the new EUCAST definitions of susceptibility testing categories S, I and R took effect. The changes in the I category have considerable clinical impact because they lead to major changes in the antibiogram, and misinterpretation may result in inappropriate selection and dosing of antibiotics hampering effective treatment of infectious diseases. We assessed if German physicians are aware of the new definitions and their consequences. We conducted a nationwide web-based survey to assess the knowledge on the new definitions of S, I and R. The survey was addressed to clinicians across all medical specialties working in Germany and was open from May 9th to July 30th 2019. The answers of 902 participants were included in the analysis. Most participants were employed at hospitals (79.3%) and had already completed specialist training (86.1%). The predominant specialty was internal medicine (50.6%). Of all participants, 45.7% did not know that there was a change in the definitions of S, I and R, and 65.4% did not feel well-informed about the changes. When the participants had to identify true and false statements regarding the new I, substantial knowledge gaps were apparent. Worst results were achieved by those physicians who are not employed in a hospital but work in their own practice. Our survey shows that German physicians are insufficiently informed about the new definitions of S, I and R. Further education is strongly needed to ensure optimal treatment of infectious diseases.

Turning a Collagenesis-Inducing Peptide Into a Potent Antibacterial and Antibiofilm Agent Against Multidrug-Resistant Gram-Negative Bacteria.

Antimicrobial resistance is becoming one the most serious health threats worldwide, as it not only hampers effective treatment of infectious diseases using current antibiotics, but also increases the risks of medical procedures like surgery, transplantation, bone and dental implantation, chemotherapy, or chronic wound management. To date, there are no effective measures to tackle life-threatening nosocomial infections caused by multidrug resistant bacterial species, of which Gram-negative species within the so-called “ESKAPE” pathogens are the most worrisome. Many such bacteria are frequently isolated from severely infected skin lesions such as diabetic foot ulcers (DFU). In this connection, we are pursuing new peptide constructs encompassing antimicrobial and collagenesis-inducing motifs, to tackle skin and soft tissue infections by exerting a dual effect: antimicrobial protection and faster healing of the wound. This produced peptide 3.1-PP4 showed MIC values as low as 1.0 and 2.1 μM against Escherichia coli and Pseudomonas aeruginosa, respectively, and low toxicity to HFF-1 human fibroblasts. Remarkably, the peptide was also potent against multidrug-resistant isolates of Klebsiella pneumoniae, E. coli, and P. aeruginosa (MIC values between 0.5 and 4.1 μM), and hampered the formation of/disaggregated K. pneumoniae biofilms of resistant clinical isolates. Moreover, this notable hybrid peptide retained the collagenesis-inducing behavior of the reference cosmeceutical peptide C16-PP4 (“Matrixyl”). In conclusion, 3.1-PP4 is a highly promising lead toward development of a topical treatment for severely infected skin injuries.

Occupational Exposure to Antibiotics in Poultry Feeding Farms.

Today, antibiotics are essential for effective treatment of infectious diseases both in human and veterinary medicine. The increasing development and distribution of antibiotic-resistant microorganisms are subject of concern. In some sectors of animal agriculture, such as poultry feeding farms, the application of antibiotics and hence occupational exposure is inevitable. In the past, numerous studies focussed on the occurrence of antibiotic-resistant bacteria in livestock farming, but little attention was paid to the employees. The exposure of workers to antibiotics was the focus of the study detailed in this article. Four biomonitoring campaigns monitoring systemic exposure of workers to antibiotics were run at two farms over four fattening periods. Urine samples of potentially affected employees were sampled and analysed for the antibiotics of interest by liquid chromatography-mass spectrometry. The highest antibiotic concentrations detected in urine samples exceeded the minimum inhibitory concentration of some bacteria strains. In some cases, the amount of antibiotics excreted over a time-period of 24 h indicated the exceedance of the tolerable daily intake.

Bioinspired and Biomimetic Nanotherapies for the Treatment of Infectious Diseases.

There are still great challenges for the effective treatment of infectious diseases, although considerable achievement has been made by using antiviral and antimicrobial agents varying from small-molecule drugs, peptides/proteins, to nucleic acids. The nanomedicine approach is emerging as a new strategy capable of overcoming disadvantages of molecular therapeutics and amplifying their anti-infective activities, by localized delivery to infection sites, reducing off-target effects, and/or attenuating resistance development. Nanotechnology, in combination with bioinspired and biomimetic approaches, affords additional functions to nanoparticles derived from synthetic materials. Herein, we aim to provide a state-of-the-art review on recent progress in biomimetic and bioengineered nanotherapies for the treatment of infectious disease. Different biomimetic nanoparticles, derived from viruses, bacteria, and mammalian cells, are first described, with respect to their construction and biophysicochemical properties. Then, the applications of diverse biomimetic nanoparticles in anti-infective therapy are introduced, either by their intrinsic activity or by loading and site-specifically delivering various molecular drugs. Bioinspired and biomimetic nanovaccines for prevention and/or therapy of infectious diseases are also highlighted. At the end, major translation issues and future directions of this field are discussed.

Drug delivery systems designed to overcome antimicrobial resistance.

Antimicrobial resistance has emerged as a huge challenge to the effective treatment of infectious diseases. Aside from a modest number of novel anti-infective agents, very few new classes of antibiotics have been successfully developed for therapeutic use. Despite the research efforts of numerous scientists, the fight against antimicrobial (ATB) resistance has been a longstanding continued effort, as pathogens rapidly adapt and evolve through various strategies, to escape the action of ATBs. Among other mechanisms of resistance to antibiotics, the sophisticated envelopes surrounding microbes especially form a major barrier for almost all anti-infective agents. In addition, the mammalian cell membrane presents another obstacle to the ATBs that target intracellular pathogens. To negotiate these biological membranes, scientists have developed drug delivery systems to help drugs traverse the cell wall; these are called "Trojan horse" strategies. Within these delivery systems, ATB molecules can be conjugated with one of many different types of carriers. These carriers could include any of the following: siderophores, antimicrobial peptides, cell-penetrating peptides, antibodies, or even nanoparticles. In recent years, the Trojan horse-inspired delivery systems have been increasingly reported as efficient strategies to expand the arsenal of therapeutic solutions and/or reinforce the effectiveness of conventional ATBs against drug-resistant microbes, while also minimizing the side effects of these drugs. In this paper, we aim to review and report on the recent progress made in these newly prevalent ATB delivery strategies, within the current context of increasing ATB resistance.

Biomimetic Bacterial Identification Platform Based on Thermal Transport Analysis Through Surface Imprinted Polymers: From Proof of Principle to Proof of Application

Accurate and sensitive detection of bacteria is crucial in medicine for diagnosis and effective treatment of infectious diseases. Current state‐of‐the art methods consist of either traditional time consuming microbiological analysis or rapid, sensitive molecular techniques that require expensive readout equipment. In previous work, the authors of this paper combined synthetic bacteria receptors, so‐called surface imprinted polymers (SIPs), with a novel thermal biosensor readout methodology for the detection of bacteria in urine. In this follow‐up study, the potential of the method for application in urinary tract infection (UTI) diagnosis is further studied. The reproducibility of the method is assessed by expanding the study and analyzing the sensor's performance in urine samples obtained from four healthy adults. The samples are spiked with increasing concentrations of Escherichia coli to obtain different dose‐response curves. The results of this study show that the method is reproducible over the studied population and variables such as age, gender and osmolality do not seem to influence the test. All results fall within the previously established dynamic range of 104–105 bacteria mL−1 which fits well within the diagnostic window of classical microbiological UTI tests. Further tests conducted on a urine sample 24 h after spiking illustrate the problem with traditional microbiology tests as the sensor response has significantly decreased due to the presence of a significant amount of dead bacteria in the day‐old sample. These results confirm that fast, point‐of‐care analysis of fresh urine samples is advantageous over classic laborious techniques in terms of accurate diagnosis.

Acute toxicity parameters of a highly-dispersive silica and pgmg-gc composite in mice after intragastric administration

The emerging and steady increase of microbes that are resistant to antimicrobial treatments has become a global public health concern that threatens the effective treatment of infectious diseases, therefore, the development of new medicines with antimicrobial properties is one of the priorities of the health systems.&#x0D; Cationic detergents, which, as a result of the combination of their surface activity and bactericidal properties, are promising for use in pharmacy and medicine. One of the representatives of the cationic surfactant group is polyhexamethylene guanidine hydrochloride (PGMG-GC) which was shown to be less toxic compared to some other disinfectants and effective against a wide spectrum of microbes.&#x0D; The aim of the study was to determine the acute toxicity parameters of a highly-dispersive silica (HDS) and PGMG-GC composite in mice after intragastric administration.&#x0D; The study was carried out on 23 BALB/c female mice weighing 18–22 g. To determine the toxicity, the animals were divided into the following groups. The first group was intragastrically injected with a composite of HDS and PGMG-GH, the second group was given a suspension of HDS, the third group was given a solution of PGMG-GC, and the fourth (control) group was treated with water for injection.&#x0D; The mass of the animals was determined before and on the 3rd, 7th, and 14th day after the composite administration. Administration of PGMG-GC or PGMG-GC + HDS composite caused significant decrease in body weight at 3rd and 7th day compared to control with further normalization on day 14. No significant changes of body weight were found in HDS group.&#x0D; No death of mice occurred after a single intragastric injection of the HDS + PGMG-GC composite during 14 days of the study. For the solution of PGMG-GC (without HDS), lethal cases were reported 2 h after the treatment at a dose level of 400 mg/kg. The condition of the animals survived normalized and, by the day 14, it corresponded to that in the control group for the most of the signs of toxicity indicating the reversibility of the toxic effect of PGMG-GC.&#x0D; Therefore, PGMG-GC is less toxic whet it is used as a part of the composite. Since no lethal cases were reported after a single intragastric administration of the composite at a dose of 2 000 mg/kg of body weight, the composite HDS + PGMG-GC appears to be low toxic according to the classification of substances by toxicity.

Antibiotic Stimulation of a Bacillus subtilis Migratory Response.

Competitive interactions between bacteria reveal physiological adaptations that benefit fitness. Bacillus subtilis is a Gram-positive species with several adaptive mechanisms for competition and environmental stress. Biofilm formation, sporulation, and motility are the outcomes of widespread changes in a population of B.subtilis. These changes emerge from complex, regulated pathways for adapting to external stresses, including competition from other species. To identify competition-specific functions, we cultured B.subtilis with multiple species of Streptomyces and observed altered patterns of growth for each organism. In particular, when plated on agar medium near Streptomyces venezuelae, B.subtilis initiates a robust and reproducible mobile response. To investigate the mechanistic basis for the interaction, we determined the type of motility used by B.subtilis and isolated inducing metabolites produced by S.venezuelae. Bacillus subtilis has three defined forms of motility: swimming, swarming, and sliding. Streptomyces venezuelae induced sliding motility specifically in our experiments. The inducing agents produced by S.venezuelae were identified as chloramphenicol and a brominated derivative at subinhibitory concentrations. Upon further characterization of the mobile response, our results demonstrated that subinhibitory concentrations of chloramphenicol, erythromycin, tetracycline, and spectinomycin all activate a sliding motility response by B.subtilis. Our data are consistent with sliding motility initiating under conditions of protein translation stress. This report underscores the importance of hormesis as an early warning system for potential bacterial competitors and antibiotic exposure. IMPORTANCE Antibiotic resistance is a major challenge for the effective treatment of infectious diseases. Identifying adaptive mechanisms that bacteria use to survive low levels of antibiotic stress is important for understanding pathways to antibiotic resistance. Furthermore, little is known about the effects of individual bacterial interactions on multispecies communities. This work demonstrates that subinhibitory amounts of some antibiotics produced by streptomycetes induce active motility in B.subtilis, which may alter species interaction dynamics among species-diverse bacterial communities in natural environments. The use of antibiotics at subinhibitory concentrations results in many changes in bacteria, including changes in biofilm formation, small-colony variants, formation of persisters, and motility. Identifying the mechanistic bases of these adaptations is crucial for understanding how bacterial communities are impacted by antibiotics.

Andrographolide disrupts meiotic maturation by blocking cytoskeletal reorganisation and decreases the fertilisation potential of mouse oocytes.

Andrographolide (AG) is a diterpenoid lactone isolated from the stem and leaves of Andrographis paniculata Nees that is used for the effective treatment of infectious diseases in Asian countries. Previous studies have reported adverse effects of AG on female fertility in rodents; however, the underlying mechanisms are unknown. The aim of the present study was to investigate the effects of AG on the IVM of mouse oocytes and their fertilisation potential. Immature oocytes incubated for 6, 14 or 24h in medium containing 5, 10 or 20μM AG showed time- and dose-dependent decreases in maturation rates compared with the control group. Immunostaining revealed that AG exposure disrupted spindle organisation and migration, as well as actin cap formation and cytokinesis. Furthermore, most oocytes exposed to 20μM AG underwent apoptosis, and the few oocytes exposed to 5 or 10μM AG that reached MII exhibited lower fertilisation rates after intracytoplasmic sperm injection. The findings of the present study suggest that AG may disrupt mouse oocyte meiotic maturation by blocking cytoskeletal reorganisation, and may thus have an adverse effect on female fertility.

Glycyrrhizic Acid Decreases Gentamicin-Resistance in Vancomycin-Resistant Enterococci.

The resistance of commensal bacteria against first and second line antibiotics has reached an alarming level in many parts of the world and endangers the effective treatment of infectious diseases. Particularly vancomycin-resistant Enterococcus faecium represents an increasing clinical problem in the treatment of infectious diseases and hinders adequate antibiotic stewardship. In consideration of the lack of novel antibiotic compounds, the development of resistance-modifying agents, however, can mitigate the spread of bacterial drug resistance and might possibly extend the useful application indices of an existing licensed antibiotic. Given that saponins modify the local chemical environment at cell membranes and might modify the uptake or mode of action of antibiotics in bacteria, we investigated the influence of the triterpenoid saponin glycyrrhizic acid of Glycyrrhiza glabra on the susceptibility of vancomycin-resistant enterococci against the aminoglycoside antibiotic gentamicin in 47 clinical isolates by applying the checkerboard method. The fractional inhibitory concentration indices values were determined between 0.016 and ≤ 0.5 (synergy is accepted with values ≤ 0.5). Glycyrrhizic acid at the subinhibitory concentration of 2.4 mM was found to reduce the minimal inhibitory concentration of gentamicin in intrinsically resistant E. faecium strains down to 6.25 % of the minimal inhibitory concentration of gentamicin alone, whereas relatively low concentrations of glycyrrhizic acid (18 µM) resulted in increased susceptibilities for some E. faecium isolates to gentamicin. In conclusion, our study points towards a therapeutic potential of glycyrrhizic acid in co-application with gentamicin for defined local bacterial infections caused by vancomycin resistant Enterococcus strains.

CAUSAL TREATMENT OF CONGENITAL CYTOMEGALOVIRUS INFECTION: CURRENT ACHIEVEMENTS AND ROUTINE PRACTICE

The key factor for the effective treatment of infectious diseases is timely causal treatment [1, 2]. However, due to various reasons, the arsenal of etiotropic drugs for the treatment of congenital infections (CIs) has been significantly small [3–6]. At the same time, in the treatment of bacterial CIs (congenital syphilis, congenital listeriosis, congenital Streptococcus agalactiae infection, congenital chlamydiosis, congenital ureaplasmosis, congenitan mycoplasmosis and other), only some of the effective antibiotics are not safe enough for use in newborns. What is more, until recently, there were practically no etiotropic therapies except Aciclovir for the treatment of viral CIs [2–6]. In view of the fact that cytomegalovirus infection (CMV) is the most common viral CI (in the US, it is diagnosed in 1% of all live births), the absence of etiotropic therapies has been particularly critical for the management of congenital CMV infection [2].

Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting

A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.

Saponins increase susceptibility of vancomycin-resistant enterococci to antibiotic compounds

The resistance of commensal bacteria to first and second line antibiotics has reached an alarming level in many parts of the world and endangers the effective treatment of infectious diseases. In this study, the influence of the plant-derived natural saponins glycyrrhizic acid, β-aescin, α-hederin, hederacoside C, and primulic acid 1 on the susceptibility of vancomycin-resistant enterococci (VRE) against antibiotics of clinical relevance was investigated in 20 clinical isolates. Furthermore, the antibacterial properties of saponins under study against VRE were determined in vitro. Results reveal that the susceptibility of VRE against gentamicin, teicoplanin, and daptomycin was enhanced in the presence of the saponin glycyrrhizic acid. Most importantly, glycyrrhizic acid (1 mg/ml) diminished the minimal inhibitory concentration (MIC) of gentamicin in gentamicin low-level intrinsic resistant VRE from 2 - >8 mg/l to ≤ 0.125-1 mg/l. The adding of β-aescin, α-hederin, hederacoside C, and primulic acid 1 to the antibiotics under study showed, compared to glycyrrhizic acid, less influence on the antibiotic potency. Only glycyrrhizic acid (1 mg/ml) and α‑hederin (0.2 mg/ml) showed weak antibacterial properties against the clinical isolates. Our study points towards a therapeutic potential of saponins in the coapplication with antibiotics for bacterial infections.