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Lymphatic filariasis (lympoedema and hydrocoele) and onchocerciasis (dermatitis and ocular inflammation) caused by the parasitic filarial nematodes , spp. and lead to severe morbidity in developing tropical countries. Mass drug administration (MDA) programmes use ivermectin or diethylcarbamazine, often combined with albendazole, with the aim to eliminate filarial diseases. However, these drugs primarily only kill the first stage larvae, the microfilariae. Removal of the parasites’ mutualistic endosymbionts of the genus using anti-rickettsial drugs results in permanent worm sterility and death of the adult worms. Since it is currently not compatible with mass drug administration due to the comparatively long treatment time of 4–6 weeks, doxycycline has been recommended for physician-monitored treatment of individuals. For individuals suffering from filarial pathology, the use of doxycycline is the first drug to have the additional advantage of improving lymphoedema. However, new drugs and regimes need to be in the pipeline in order to tackle the upcoming or already existing problem areas, such as those with ivermectin resistance, areas coendemic for loiasis, or end-game scenarios. Here, we summarize current treatment options and review current research approaches for optimization of anti-helminthic therapy, including the exploration of optimized delivery strategies of ivermectin and albendazole, the discovery and development of new antibiotics for anti-wolbachial chemotherapy and macrofilaricidal antihelminthics.

Obligate intracellular endobacteria of the genus Wolbachia are widespread in arthropods and several filarial nematodes. Control programs for vector-borne diseases (dengue, Zika, malaria) and anti-filarial therapy with antibiotics are based on this important endosymbiont. Investigating Wolbachia, however, is impeded by the need for host cells. In this study, the requirements for Wolbachia wAlbB growth in a host cell-free in vitro culture system were characterized via qPCRs. A cell lysate fraction from Aedes albopictus C6/36 insect cells containing cell membranes and medium with fetal bovine serum were identified as requisite for cell-free replication of Wolbachia. Supplementation with the membrane fraction of insect cell lysate increased extracellular Wolbachia replication by 4.2-fold. Replication rates in the insect cell-free culture were lower compared to Wolbachia grown inside insect cells. However, the endobacteria were able to replicate for up to 12 days and to infect uninfected C6/36 cells. Cellfree Wolbachia treated with the lipid II biosynthesis inhibitor fosfomycin had an enlarged phenotype, seen previously for intracellular Wolbachia in C6/36 cells, indicating that the bacteria were unable to divide. In conclusion, we have developed a cell-free culture system in which Wolbachia replicate for up to 12 days, providing an in vitro tool to elucidate the biology of these endobacteria, e.g., cell division by using compounds that may not enter the C6/36 cells. A better understanding of Wolbachia biology, and in particular host-symbiont interactions, is key to the use of Wolbachia in vector control programs and to future drug development against filarial diseases. [ABSTRACT FROM AUTHOR]

Chlamydial infections and diseases caused by filarial nematodes are global health concerns. However, treatment presents challenges due to treatment failures potentially caused by persisting Chlamydia and long regimens against filarial infections accompanied by low compliance. A new treatment strategy could be the targeting of the reduced peptidoglycan structures involved in cell division in the obligate intracellular bacteria Chlamydia and Wolbachia, the latter being obligate endosymbionts supporting filarial development, growth, and survival. Here, cell culture experiments with C. trachomatis and Wolbachia showed that the nucleoside antibiotics muraymycin and carbacaprazamycin interfere with bacterial cell division and induce enlarged, aberrant cells resembling the penicillin-induced persistence phenotype in Chlamydia. Enzymatic inhibition experiments with purified C. pneumoniae MraY revealed that muraymycin derivatives abolish the synthesis of the peptidoglycan precursor lipid I. Comparative in silico analyses of chlamydial and wolbachial MraY with the corresponding well-characterized enzyme in Aquifex aeolicus revealed a high degree of conservation, providing evidence for a similar mode of inhibition. Muraymycin D2 treatment eradicated persisting non-dividing C. trachomatis cells from an established penicillin-induced persistent infection. This finding indicates that nucleoside antibiotics may have additional properties that can break bacterial persistence. [ABSTRACT FROM AUTHOR]

Toxicological studies are a part of the drug development process and the preclinical stages, for which suitable vehicles ensuring easy and safe administration are crucial. However, poor aqueous solubility of drugs complicates vehicle screening for oral administration since non-aqueous solvents are often not tolerable. In the case of the anti-infective corallopyronin A, currently undergoing preclinical investigation for filarial nematode and bacterial infections, commonly used vehicles such as polyethylene glycol 200, aqueous solutions combined with cosolvents or solubilizers, or aqueous suspension have failed due to insufficient tolerability, solubility, or the generation of a non-homogeneous suspension. To this end, the aim of the study was to establish an alternative approach which offers suitable tolerability, dissolution, and ease of handling. Thus, a corallopyronin A-mesoporous silica formulation was successfully processed and tested in a seven-day toxicology study focused on Beagle dogs, including a toxicokinetic investigation on day one. Sufficient tolerability was confirmed by the vehicle control group. The vehicle enabled high-dose levels resulting in a low-, middle-, and high-dose of 150, 450, and 750 mg/kg. Overall, it was possible to achieve high plasma concentrations and exposures, leading to a valuable outcome of the toxicology study and establishing mesoporous silica as a valuable contender for challenging drug candidates. [ABSTRACT FROM AUTHOR]

In summary, we have attempted to define several points that argue for a different species name for the Wolbachia in nematodes. Until the endobacteria in the genus Wolbachia are formally characterized, typed and named according to the Bacteriological Code (Lapage et al., 1992), we believe that there is enough evidence to support naming, for purposes of discussion, the Wolbachia of supergroups C and D after a key host species in each supergroup, e.g. 'Wolbachia volvulus' (Onchocerca volvulus) and 'Wolbachia malayi' (Brugia malayi), respectively. The endobacteria of Mansonella spp., in Wolbachia supergroup F, which have both nematode and arthropod hosts, should remain W. pipientis until more study clarifies their phylogeny. By assigning different names to Wolbachia of the C and D supergroups, their unique biology and phylogeny will be better highlighted and the taxonomy of Wolbachia will be more in line with the biology of these fascinating bacteria.

Methicillin-resistant Staphylococcus aureus (MRSA) is a World Health Organization's high priority pathogen organism, with an estimated > 100,000 deaths worldwide in 2019. Thus, there is an unmet medical need for novel and resistance-breaking anti-infectives. The natural product Co-rallopyronin A (CorA), currently in preclinical development for filariasis, is efficacious against MRSA in vitro. In this study, we evaluated the pharmacokinetics of CorA after dosing in mice. Furthermore, we determined compound concentrations in target compartments, such as lung, kidney and thigh tissue, using LC-MS/MS. Based on the pharmacokinetic results, we evaluated the pharmacodynamic profile of CorA using the standard neutropenic thigh and lung infection models. We demonstrate that CorA is effective in both standard pharmacodynamic models. In addition to reaching effective levels in the lung and muscle, CorA was detected at high levels in the thigh bone. The data presented herein encourage the further exploration of the additional CorA indications treatment of MRSA- and methicillin-sensitive S. aureus- (MSSA) related infections. [ABSTRACT FROM AUTHOR]