Semisynthetic Tetracycline Research Articles

Fixed Drug Eruption Due to Doxycycline Postexposure Prophylaxis

Doxycycline is a semi-synthetic antibiotic in the tetracycline family. The three common subtypes of tetracyclines include naturally occurring, semi-synthetic, and new agents. Each subtype shares specific commonalities but is substantially different in various clinical applications. The mechanism of antimicrobial activity is the same across subtypes. The structural changes to the core naphthacene ring do not alter the mechanism of action but are thought to alter the rates of adverse effects and mechanisms of resistance. Tetracyclines as a class are known to cause fixed drug eruptions, but the majority of these adverse effects were associated with naturally occurring tetracyclines. Semi-synthetic tetracyclines have limited reports of fixed drug eruptions. Here, we present a case of fixed drug eruption in a patient who previously had multiple treatment courses with doxycycline. The case involves the use of doxycycline not for the treatment of an infection but as postexposure prophylactic (PEP) antibiotic therapy to prevent the acquisition of a sexually transmitted infection. Doxycycline PEP has been shown to reduce the rate of bacterial sexually transmitted infection in men who have sex with men (MSM). Doxycycline PEP is a single dose taken orally within 24–72 h of unprotected sexual intercourse. The dosing structure allows for ease of adherence but also repeatedly exposes individuals to doxycycline, putting them at risk for adverse events such as fixed drug eruptions, as illustrated by this case report.

C9-Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α-Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration.

Doxycycline, a semi-synthetic tetracycline, is a widely used antibiotic for treating mild-to-moderate infections, including skin problems. However, its anti-inflammatory and antioxidant properties, combined with its ability to interfere with α-synuclein aggregation, make it an attractive candidate for repositioning in Parkinson's disease. Nevertheless, the antibiotic activity of doxycycline restricts its potential use for long-term treatment of Parkinsonian patients. In the search for non-antibiotic tetracyclines that could operate against Parkinson's disease pathomechanisms, eighteen novel doxycycline derivatives were designed. Specifically, the dimethyl-amino group at C4 was reduced, resulting in limited antimicrobial activity, and several coupling reactions were performed at position C9 of the aromatic D ring, this position being one of the most reactive for introducing substituents. Using the Thioflavin-T assay, we found seven compounds were more effective than doxycycline in inhibiting α-synuclein aggregation. Furthermore, two of these derivatives exhibited better anti-inflammatory effects than doxycycline in a culture system of microglial cells used to model Parkinson's disease neuroinflammatory processes. Overall, through structure-activity relationship studies, we identified two newly designed tetracyclines as promising drug candidates for Parkinson's disease treatment.

Antibiotic resistance of P. aeruginosa in the presence and absence of pyocyanin pigment

Purpose: study of antibiotic resistance of Р. aeruginosa strains in the presence and absence of pyocyanin pigment. Materials and methods. Bacteriological studies of pathological material from "asphyxiated embryos", sick chickens and forcibly killed or dead adult birds were carried out according to generally accepted methods. Cultures from bone, brain, heart, liver, spleen, gall bladder, muscles and other organs were carried out on simple, selective and differential diagnostic nutrient media. The sensitivity of P. aeruginosa isolates to antibacterial drugs was determined by diffusion in agar according to the generally accepted method. The results. The obtained results of studies by the diffusion method in agar indicate that the proportion of resistant to the studied antibiotics among non-pigmented isolates was on average 79.00 % (60-100) %, and among strains that formed pyocyanin - 51.00 % (25-100) %. 60.00 % - 90.00 % of resistant non-pigmented isolates were found to fluoroquinolones, 60.00-70.00 % to cephalosporins, 60.00-97.00 % to aminoglycosides. To representatives of semisynthetic penicillins, tetracyclines, and macrolides - 100 % of resistant isolates that did not synthesize pyocyanin were found. Among P. aeruginosa isolates that synthesized pigment, 25.00-40.00 % were resistant to fluoroquinolones, 30.00-35.00 % to cephalosporins, 25.00-50.00 % to aminoglycosides, representatives semi-synthetic penicillins, tetracyclines, macrolides - 100 % of the studied strains. Conclusions. The absence of pigment formation in P. aeruginosa isolates, obtained in association with bacterial pathogens, is not accompanied by the absence of antibiotic resistance. 28 % more antibiotic-resistant isolates were found among non-pigmented isolates compared to isolates that synthesize pyocyanin pigment. The data presented emphasize the need for the use of differential media for the isolation of P. aeruginosa in order to identify non-pigmented strains and prescribe appropriate treatment, which, accordingly, will prevent the spread of latent forms of infection

The application of electrosprayed minocycline-loaded PLGA microparticles for the treatment of glioblastoma.

The survival of patients with glioblastoma multiforme (GBM), the most common and invasive form of malignant brain tumors, remains poor despite advances in current treatment methods including surgery, radiotherapy, and chemotherapy. Minocycline is a semi-synthetic tetracycline derivative that has been widely used as an antibiotic and more recently, it has been utilized as an antiangiogenic factor to inhibit tumorigenesis. The objective of this study was to investigate the utilization of electrospraying process to fabricate minocycline-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles with high drug loading and loading efficiency and to evaluate their ability to induce cell toxicity in human glioblastoma (i.e., U87-MG) cells. The results from this study demonstrated that solvent mixture of dicholoromethane (DCM) and methanol is the optimal solvent combination for minocycline and larger amount of methanol (i.e., 70:30) resulted in a higher drug loading. All three solvent ratios of DCM:methanol tested produced microparticles that were both spherical and smooth, all in the micron size range. The electrosprayed microparticles were able to elicit a cytotoxic response in U87-MG glioblastoma cells at a lower concentration of drug compared to the free drug. This work provides proof of concept to the hypothesis that electrosprayed minocycline-loaded PLGA microparticles can be a promising agent for the treatment of GBM and could have potential application for cancer therapies.

Structural preservation does not ensure function at sensory Ia - motoneuron synapses following peripheral nerve injury and repair.

Injury that severs peripheral nerves often results in long-lasting motor behavioral deficits and in reorganization of related spinal motor circuitry, neither of which reverse even after nerve regeneration. Stretch areflexia and gait ataxia, for example, emerges from a combination of factors including degeneration of Ia - motoneuron synapses between peripherally damaged Ia muscle spindle afferents and motoneurons. Based on evidence that nerve injury acts through immune responses to induce synapse degeneration, we hypothesized that suppressing inflammatory responses would preserve Ia - motoneuron connectivity and aid in restoring normal function. We tested our hypothesis by administering the anti-inflammatory agent minocycline in male and female rats following axotomy of a peripheral nerve. The connectivity of Ia - motoneuron synapses was then assessed both structurally and functionally at different time points. We found that minocycline treatment overcame the physical loss of Ia contacts on motoneurons which are otherwise lost after axotomy. While necessary for functional recovery, synaptic preservation was not sufficient to overcome functional decline expressed as smaller than normal stretch-evoked synaptic potentials (SSP) evoked monosynaptically at Ia - motoneuron connections and an absence of the stretch reflex. These findings demonstrate a limited capacity of minocycline to rescue normal sensorimotor behavior, illustrating that structural preservation of synaptic connectivity does not ensure normal synaptic function.Significance Statement:Here we demonstrate that acute treatment with the semisynthetic tetracycline anti-inflammatory agent minocycline permanently prevents the comprehensive loss of synaptic contacts made between sensory neurons and spinal motoneurons following peripheral nerve injury and eventual regeneration. Treatment failed, however, to rescue normal function of those synapses or the reflex circuit they mediate. These findings demonstrate that preventing synaptic disconnection alone is not sufficient to restore neural circuit operation and associated sensorimotor behaviors.

Abstract 2000: Injectable alginate scaffolds for the delivery of minocycline for the treatment of glioblastoma

Abstract Glioblastoma Multiforme (GBM) is a Grade IV malignant brain cancer that is associated with a high recurrence and low survival rate amongst affected patients. Despite advances in the different methods of therapy, the prognosis for GBM has not improved through the years and, thus, alternative treatment methods for GBM are needed. Minocycline (MINO) is known as a semi-synthetic tetracycline that serves as an antibiotic and has also been shown to be able to suppress angiogenesis for GBM treatment. Collected from brown seaweed, alginate is a biodegradable polysaccharide that can be used to form a hydrogel for drug delivery due to its biocompatibility properties. Injectable alginate scaffolds may be a promising component for an adjuvant treatment method against GBM as the injectability property of the scaffold will allow for the site of interest to be filled precisely after tumor resection. The objective of this study is to develop injectable alginate scaffolds for the delivery of MINO for the treatment of GBM. The effects of the concentration of sodium alginate (SA) and calcium carbonate (CaCO3) (i.e., 0.75, 1.00, 1.50, and 2.00 wt./vol.%) with a 0.25 wt./vol.% of glucono-delta lactone (GDL) on the pH, gelation time, dimensions, degradation, and drug release kinetics of alginate scaffolds were investigated. Injectable alginate scaffolds were fabricated by dissolving SA and CaCO3 (1:1) in water, homogenized with GDL for 20 sec., and then injected into a 24-well plate to develop uniform scaffolds. Their properties were evaluated by testing pH values via a pH meter, timing gelation with a digital timer, utilizing a digital microcaliper to investigate dimensions, an analytical scale to evaluate the mass of dried scaffolds to determine scaffold degradation, and evaluating the release rate of MINO using a microplate reader at a wavelength of 350 nm. As the concentration of SA and CaCO3 increased, an increase in pH, gelation time, and overall stability of the scaffold were observed. All four concentrations of SA and CaCO3 tested resulted in scaffolds with desired pH and workable gelation time; however, the 1 wt./vol.% group may be the most ideal as an optimal pH was reached after 10 minutes and the gelation time for these scaffolds was ~8 minutes. Lower concentration scaffolds (0.75 and 1.00 wt./vol.%) degraded faster in comparison to those made with higher concentrations. Drug release kinetics data revealed that the scaffolds can sustain short term release but could be improved by incorporating the drug into micro or nanoparticles before incorporation into the scaffolds. In conclusion, the injectable alginate scaffolds developed in this study may be promising biomaterials for the delivery of drugs for GBM treatment. Citation Format: Kaitlyn D. Ybáñez, Marco A. Arriaga, Rene N. Rico, Theresia Rookstool, Sue Anne Chew. Injectable alginate scaffolds for the delivery of minocycline for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2000.

Doxycycline attenuates l-DOPA-induced dyskinesia through an anti-inflammatory effect in a hemiparkinsonian mouse model.

The pharmacological manipulation of neuroinflammation appears to be a promising strategy to alleviate l-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). Doxycycline (Doxy), a semisynthetic brain-penetrant tetracycline antibiotic having interesting anti-inflammatory properties, we addressed the possibility that this compound could resolve LID in l-DOPA-treated C57BL/6 mice presenting either moderate or intermediate lesions of the mesostriatal dopaminergic pathway generated by intrastriatal injections of 6-OHDA. Doxy, when given subcutaneously before l-DOPA at doses of 20mgkg-1 and 40mgkg-1, led to significant LID reduction in mice with moderate and intermediate dopaminergic lesions, respectively. Importantly, Doxy did not reduce locomotor activity improved by l-DOPA. To address the molecular mechanism of Doxy, we sacrificed mice with mild lesions 1) to perform the immunodetection of tyrosine hydroxylase (TH) and Fos-B and 2) to evaluate a panel of inflammation markers in the striatum, such as cyclooxygenase-2 and its downstream product Prostaglandin E2 along with the cytokines TNF-α, IL-1β and IL-6. TH-immunodetection revealed that vehicle and Doxy-treated mice had similar striatal lesions, excluding that LID improvement by Doxy could result from neurorestorative effects. Importantly, LID inhibition by Doxy was associated with decreased Fos-B and COX-2 expression and reduced levels of PGE2, TNF-α, and IL-1β in the dorsolateral striatum of dyskinetic mice. We conclude 1) that Doxy has the potential to prevent LID regardless of the intensity of dopaminergic lesioning and 2) that the anti-inflammatory effects of Doxy probably account for LID attenuation. Overall, the present results further indicate that Doxy might represent an attractive and alternative treatment for LID in PD.

Possible Use of Minocycline in Adjunction to Intranasal Esketamine for the Management of Difficult to Treat Depression following Extensive Pharmacogenomic Testing: Two Case Reports

The advent of intra-nasal esketamine (ESK), one of the first so called fast-acting antidepressant, promises to revolutionize the management of treatment resistant depression (TRD). This NMDA receptor antagonist has proven to be rapidly effective in the short- and medium-term course of the illness, revealing its potential in targeting response in TRD. Although many TRD ESK responders are able to achieve remission, a considerable portion of them undergo a metamorphosis of their depression into different clinical presentations, characterized by instable responses and high recurrence rates that can be considered closer to the concept of Difficult to Treat Depression (DTD) than to TRD. The management of these DTD patients usually requires a further complex multidisciplinary approach and can benefit from the valuable contribution of new personalized medicine tools such as therapeutic drug monitoring and pharmacogenetics. Despite this, these patients usually come with long and complex previous treatments history and, often, advanced and sophisticated ongoing pharmacological schemes that can make the finding of new alternative options to face the current recurrences extremely challenging. In this paper, we describe two DTD patients—already receiving intranasal ESK but showing an instable course—who were clinically stabilized by the association with minocycline, a semisynthetic second-generation tetracycline with known and promising antidepressant properties.

In Situ Effects of Doxycycline on Neuromuscular Junction in Mice.

The antibacterial mechanism of doxycycline is known, but its effects on the nerve-muscle system are still not unclear. The aim of the study was to combine molecular targets of the neuromuscular machinery using the in situ neuronal blocker effect of doxycycline, a semisynthetic second-generation tetracycline derivative, on mice neuromuscular preparations. The effects of doxycycline were assessed on presynaptic, synaptic cleft, and postsynaptic neurotransmission, along with the muscle fiber, using the traditional myographic technique. Precisely, the effects of doxycycline were categorized into "all" or "nothing" effects depending on the concentration of doxycycline used; "all" was obtained with 4 μM doxycycline, and "nothing" was obtained with 1-3 μM doxycycline. The rationale of this study was to apply known pharmacological tools against the blocker effect of 4 μM doxycycline, such as F55-6 (Casearia sylvestris), CaCl2 (or Ca2+), atropine, neostigmine, polyethylene glycol (PEG 400), and d-Tubocurarine. The evaluation of cholinesterase enzyme activity and the diaphragm muscle histology were performed, and protocols on the neuromuscular preparation submitted to indirect or direct stimuli were complementary. Doxycycline does not affect cholinesterase activity nor causes damage to skeletal muscle diaphragm; it acts on ryanodine receptor, sarcolemmal membrane, and neuronal sodium channel with a postjunctional consequence due to the decreased availability of muscle nicotinic acetylcholine receptors. In conclusion, in addition to the neuronal blocker effect of doxycycline, we showed that doxycycline acts on multiple targets. It is antagonized by F55-6, a neuronal Na+-channel agonist, and Ca2+, but not by neostigmine.

Minocycline treatment improves proteostasis during Drosophila aging via autophagy mediated by FOXO and Hsp70

Minocycline is a semi-synthetic tetracycline derivative antibiotic that has been examined for its non-antibiotic properties, such as anti-inflammatory, tumor-suppressive, and neuroprotective effects. In this study, we found that feeding minocycline to Drosophila improves proteostasis during organismal aging. Poly-ubiquitinated protein aggregates increase in the flight muscles as flies age, which are reduced in response to minocycline feeding. Minocycline feeding increases the expression of several autophagy genes and the activity of the autophagy/lysosomal pathway in Drosophila muscles. Interestingly, mutant flies lacking either FOXO or Hsp70 showed increased levels of poly-ubiquitinated protein aggregates with reduced autophagy/lysosomal activity, which was not reversed by minocycline feeding. Our findings suggest that minocycline may improve proteostasis in aging tissues via FOXO-Hsp70 axis, which highlights the multifaceted effects of minocycline as a therapeutic agent in age-associated features.

Molecular dissemination of emerging antibiotic, biocide, and metal co-resistomes in the Himalayan hot springs

Growing resistance among microbial communities against antimicrobial compounds, especially antibiotics, is a significant threat to living beings. With increasing antibiotic resistance in human pathogens, it is necessary to examine the habitats having community interests. In the present study, a metagenomic approach has been employed to understand the causes, dissemination, and effects of antibiotic, metal, and biocide resistomes on the microbial ecology of three hot springs, Borong, Lingdem, and Yumthang, located at different altitudes of the Sikkim Himalaya. The taxonomic assessment of these hot springs depicted the predominance of mesophilic organisms, mainly belonging to the phylum Proteobacteria. The enriched microbial metabolism assosiated with energy, cellular processes, adaptation to diverse environments, and defence were deciphered in the metagenomes. The genes representing resistance to semisynthetic antibiotics, e.g., aminoglycosides, fluoroquinolones, fosfomycin, vancomycin, trimethoprim, tetracycline, streptomycin, beta-lactams, multidrug resistance, and biocides such as triclosan, hydrogen peroxide, acriflavin, were abundantly present. Various genes attributing resistance to copper, arsenic, iron, and mercury in metal resistome were detected. Relative abundance, correlation, and genome mapping of metagenome-assembled genomes indicated the co-evolution of antibiotic and metal resistance in predicted novel species belonging to Vogesella, Thiobacillus, and Tepidimona genera. The metagenomic findings were further validated with isolation of microbial cultures, exhibiting resistance against antibiotics and heavy metals, from the hot spring water samples. The study furthers our understanding about the molecular basis of co-resistomes in the ceological niches and their possible impact on the environment.

Minocycline suppresses disease-associated microglia (DAM) in a model of photoreceptor cell degeneration

As the resident immune cells in the retina, microglia play important homeostatic roles in retinal immune regulation and neuroprotection. However, chronic microglia activation is a common hallmark of many degenerative retinal diseases. The semi-synthetic tetracycline antibiotic, minocycline, appears to inhibit pro-inflammatory microglia which coincides with protection against photoreceptor cell degeneration. A sub-type of microglia termed disease associated microglia (DAM) have recently been associated with a wide range of central nervous system (CNS) diseases. In this study we examine the kinetics of microglia infiltration towards the outer retina of rhodopsin knockout mice (Rho−/−) by immunofluorescence, and undertake transcriptional and spatial localization analysis of markers for evidence of both homeostatic function and appearance of DAM. We demonstrate in the Rho−/− mice, IBA1+ and P2RY12+ microglia take on an activated morphology early in disease, prior to notable photoreceptor loss and are capable of infiltrating the subretinal space. Expression of lipid processing enzyme and DAM-marker lipoprotein lipase (LPL) is primarily observed only after microglia have traversed the ONL. Administration of minocycline to Rho−/− mice induced loss of phagocytic/DAM microglia in the outer retina in vivo coinciding with photoreceptor survival and amelioration of retinal degeneration. Overall, we show that minocycline suppresses many DAM markers, in particular those associated with lipid metabolism indicating that suppression of this process is one mechanism by which minocycline protects against inflammation induced photoreceptor cell death.

Minocycline improves the functional recovery after traumatic brain injury via inhibition of aquaporin-4

Traumatic brain injury (TBI) is one of the main concerns worldwide as there is still no comprehensive therapeutic intervention. Astrocytic water channel aquaporin-4 (AQP-4) system is closely related to the brain edema, water transport at blood-brain barrier (BBB) and astrocyte function in the central nervous system (CNS). Minocycline, a broad-spectrum semisynthetic tetracycline antibiotic, has shown anti-inflammation, anti-apoptotic, vascular protection and neuroprotective effects on TBI models. Here, we tried to further explore the underlying mechanism of minocycline treatment for TBI, especially the relationship of minocycline and AQP4 during TBI treatment. In present study, we observed that minocycline efficaciously reduces the elevation of AQP4 in TBI mice. Furthermore, minocycline significantly reduced neuronal apoptosis, ameliorated brain edema and BBB disruption after TBI. In addition, the expressions of tight junction protein and astrocyte morphology alteration were optimized by minocycline administration. Similar results were found after treating with TGN-020 (an inhibitor of AQP4) in TBI mice. Moreover, these effects were reversed by cyanamide (CYA) treatment, which notably upregulated AQP4 expression level in vivo. In primary cultured astrocytes, small-interfering RNA (siRNA) AQP4 treatment prevented glutamate-induced astrocyte swelling. To sum up, our study suggests that minocycline improves the functional recovery of TBI through reducing AQP4 level to optimize BBB integrity and astrocyte function, and highlights that the AQP4 may be an important therapeutic target during minocycline treating for TBI.

Broad-host-range IncW plasmid harbouring tet(X) in Escherichia coli isolated from pigs in Japan

Tetracyclines are used in veterinary medicine for livestock. Tigecycline, a semisynthetic tetracycline derivative, is a last-resort antimicrobial used to treat multidrug-resistant Gram-negative bacterial infections. The prevalence of variants of the mobile tigecycline resistance gene tet(X) in livestock is increasing worldwide. However, the prevalence of Tet(X) among livestock in Japan is unclear. This study was conducted to clarify the prevalence of Tet(X) in pigs in Japan, focusing on isolation and molecular characterisation of plasmid-mediated tet(X)-positive Escherichia coli through retrospective analysis. We retrospectively screened for tigecycline-resistant E. coli strains isolated from pigs. The tigecycline-resistant strain and tet(X)-harbouring plasmid were characterised. The IncW plasmid harbouring the tet(X) variant [previously named as tet(X6)] was detected in one E. coli isolate from pigs (0.8%; 1/120) in 2012. The tet(X) plasmid was transferable by conjugation to the E. coli ML4909 recipient strain. Some mobile genetic elements (TnAs3 and ISVsa3) were observed in the region surrounding tet(X). The tet(X)-harbouring plasmid shared a conserved backbone with IncW plasmid R388, which is a broad-host-range plasmid. The emergence and spread of tet(X) variants in Enterobacterales poses a public-health concern. To the best of our knowledge, this is the first report of the emergence of an IncW plasmid harbouring tet(X). Using tetracyclines in livestock exerts selective pressure on the tet(X) plasmid; therefore, prudent use of tetracyclines is required.

FORMULATION DEVELOPMENT AND EVALUATION OF SITE SPECIFIC PERIODONTAL GELS

Periodontal pockets act as a natural reservoir filled with gingival crevicular fluid for the controlled release of antimicrobials directly. This work reflects the present status of nonsurgical controlled local intrapocket delivery of antimicrobials in the treatment of periodontitis. These sites have specialty in terms of anatomy, permeability and their ability to retain a delivery system for a desired length of time. A number of antimicrobial products and the composition of the delivery systems, its use, clinical results, and their release are summarized. In the present study development of site specific periodontal drug delivery system was developed for Metronidazole and Minocycline HCl. Metronidazole is an important active substance that has been widely used in the treatment of some protozoal and anaerobic bacterial infections. Minocycline hydrochloride is a semi synthetic tetracycline, which has been primarily indicated for the treatment of Acne vulgaris. Polarizing photographs of gel lacking CMC, PVP and a gel encircling 10% CMC and 5% PVP are naked. Photographs demonstrated a dark background in the instance of plain gel, though some fan like formations were supposed in the polarizing photograph of the P5C10 formulation. The consequence of drug(s) concentration on gelation and gel melting is done. The gelation temperature was miserable in the company of drug(s) and conical linearly with its growing concentration, while the melting temperature amended with the concentration of drug(s). The mechanical properties of the augmented formulations for the supervision of periodontal disease were resolute.

Doxycycline and minocycline in Helicobacter pylori treatment: A systematic review and meta-analysis.

The decreasing Helicobacter pylori eradication rate and the increasing antibiotic resistance trend are of great concern. Therefore, new and effective therapies are needed for H.pylori infection. We conducted a systematic review and meta-analysis to assess the efficacy and safety of semisynthetic tetracycline regimens in H.pylori treatment. PubMed, EMBASE, and the Cochrane library were searched. The outcome indicators were the eradication rate, risk ratio (RR, ie, the risk of the semisynthetic tetracycline regimen relative to the control), and 95% confidence interval (95% CI). Controls were patients undergoing any other treatment without semisynthetic tetracycline. Twenty-three studies with 5240 participants were included. The eradication rates of triple regimens with semisynthetic tetracyclines in most studies were less than 70% in both the intention-to-treat (ITT) and the per-protocol (PP) analyses. The pooled eradication rates of quadruple therapies with doxycycline and controls were 95% and 84% in the PP analyses, respectively. The pooled RR associated with efficacy in the quadruple therapy with doxycycline group compared with the control group was 1.12 (95% CI: 1.04-1.20) in the PP analysis. The pooled RR of side effects in the quadruple therapy with doxycycline group compared with the control group was 1.01 (95% CI: 0.65-1.55). Seven-day and ten-day quadruple therapy with doxycycline might be an optional first-line therapy. The safety of regimens containing semisynthetic tetracyclines was relatively satisfactory. However, the triple regimen is not recommended.

Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa.

Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)-/-Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.

A highly selective ratiometric fluorescent probe for doxycycline based on the sensitization effect of bovine serum albumin

Fluorescent probes with in-situ visual feature have received numerous attentions for detecting doxycycline (DC), a semisynthetic tetracycline antibiotic widely used in animal husbandry. However, reported fluorescent probes commonly fail to selectively detect DC among tetracycline antibiotics due to their structural similarity. In this work, bovine serum albumin-capped gold nanoclusters (BSA-AuNCs) were ingeniously used as the ratiometric fluorescent probe for detecting DC over other tetracycline antibiotics through the selective sensitization effect of BSA on DC. After adding DC, the red fluorescence of BSA-AuNCs almost remained unchanged, while the green fluorescence of DC also emerged under the sensitization of BSA. BSA-AuNCs showed the highest response toward DC among tetracycline antibiotics ascribed to the strongest sensitization effect of BSA on DC. BSA-AuNCs also displayed the features of simple synthesis, short response time (1 min) and low detection limit (36 nM). BSA-AuNCs were finally applied to detecting DC in fish samples, and further fabricated into test strips for ease of carrying. Thus, this work proposes an efficient strategy to design fluorescent probe for selectively detecting DC among tetracycline antibiotics.

Underlying mechanisms of the effect of minocycline against Candida albicans biofilms

Minocycline (MH) is a broad-spectrum antimicrobial agent and semisynthetic tetracycline derivative, which has been widely used in the clinic due to its efficacy. Having the strongest anti-microbial effect, MH exceeded the traditional scope of antibiotics and its previously unknown antifungal activity is also gradually being discovered. To preliminarily investigate the inhibitory effect of MH on Candida albicans (C. albicans), changes of cell growth, hyphal formation and transition, biofilm production and signaling pathway gene expression of C. albicans in the presence of MH were assessed in the present study. An XTT reduction assay was performed to quantitatively detect the metabolic activity of biofilms and evaluate the inhibition of MH on this. The results suggested that biofilm formation was clearly inhibited by 67% (P<0.0001) in the presence of 250 µg/ml MH, while mature biofilms were not significantly affected. In addition, MH inhibited the transition from yeast to hypha in a dose-dependent manner. Furthermore, reverse transcription-quantitative PCR revealed that several hyphae- and adhesion-specific genes associated with the Ras/cyclic (c)AMP/protein kinase A (PKA) pathway were differentially expressed following MH treatment, including downregulation of ras family GTPase (RAS1), adenylyl cyclase-associated protein 1 (CAP1), thiamin pyrophosphokinase 1 (TPK1), adenylate cyclase (CDC35), transcription factor (TEC1), agglutinin-like protein 3 (ALS3) and hyphal wall protein 1 (HWP1) and upregulation of EFG1 (enhanced filamentous growth protein 1 gene) and PDE2 (high-affinity phosphodiesterase gene). The most obviously changed genes were TPK1, HWP1 and RAS1, downregulated by 0.33-, 0.48- and 0.55-fold, respectively. It was suggested that MH is associated with alterations in the morphology of C. albicans, such as the repression of hypha and biofilm formation of cells, and MH affected the Ras/cAMP pathway to regulate the expression of cAMP-associated genes.

Tetracyclines, a promise for neuropsychiatric disorders: from adjunctive therapy to the discovery of new targets for rational drug design in psychiatry.

Major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, represent the leading cause of disability worldwide. Nevertheless, the current pharmacotherapy has several limitations, and a large portion of patients do not respond appropriately to it or remain with disabling symptoms overtime. Traditionally, pharmacological interventions for psychiatric disorders modulate dysfunctional neurotransmitter systems. In the last decades, compelling evidence has advocated for chronic inflammatory mechanisms underlying these disorders. Therefore, the repurposing of anti-inflammatory agents has emerged as an attractive therapeutic tool for mental disorders. Minocycline (MINO) and doxycycline (DOXY) are semisynthetic second-generation tetracyclines with neuroprotective and anti-inflammatory properties. More recently, the most promising results obtained in clinical trials using tetracyclines for major psychiatric disorders were for schizophrenia. In a reverse translational approach, tetracyclines inhibit microglial reactivity and toxic inflammation by mechanisms related to the inhibition of nuclear factor kappa B signaling, cyclooxygenase 2, and matrix metalloproteinases. However, the molecular mechanism underlying the effects of these tetracyclines is not fully understood. Therefore, the present review sought to summarize the latest findings of MINO and DOXY use for major psychiatric disorders and present the possible targets to their molecular and behavioral effects. In conclusion, tetracyclines hold great promise as (ready-to-use) agents for being used as adjunctive therapy for human neuropsychiatric disorders. Hence, the understanding of their molecular mechanisms may contribute to the discovery of new targets for the rational drug design of novel psychoactive agents.