The synthesis of 40 new monocyclic β-lactams bearing a morpholine moiety at their N1 positions is described. The structures of these compounds have been confirmed by IR, 1H-NMR, 13C-NMR, Mass spectra and Elemental analysis. The antimicrobial activities of the synthetic compounds have been tested against clinically important fungi including Candida, Aspergillus and Microsporum and Epidermophyton species by broth microdilution method as recommended by CLSI. Inhibition studies showed that some of the tested compounds, in particular those with phenoxy groups, exhibited strong antifungal activities against all tested fungi at concentrations of less than 8 μg/mL, while others only inhibited the growth of dermatophytes or Aspergillus species. These results suggest that the derivatives should be investigated further for possible use in antimicrobial products. Keywords: Antifungal, aspergillus, azetidine-2-one, candida, dermatophyte, fungi, monocyclic β-lactam, morpholine.

In recent years, vancomycin has received appreciable attention as an antibiotic drug of last resort. The generally accepted mechanism entails interference with bacterial cell wall synthesis. There is negligible attention to other modes, even though drug action is often multifaceted. This review provides a hypothesis for an additional mechanism of antibacterial action based on the polyphenol residue in the glycopeptide. The functionalities present are monophenol, resorcinol and hydroxybiphenyl, all of which have the potential to produce electron transfer (ET) metabolites capable of generating reactive oxygen species (ROS) and oxidative stress (OS). Considerable literature is presented in support of the thesis. Drug toxicity is rationalized based on the fundamental approach to vancomycin action. This review represents another example in support of the prior ET-ROS-OS unifying mechanism for anti-infective and toxic action. Novel insight may aid in improved drug design.

Inadequate use of anthelmitic drugs in livestock animals has led to therapeutic failures and to the dramatic widespread development of parasite resistance. Additional scientific knowledge on how to improve the use of available and novel molecules is required to avoid/delay resistance development. The time of parasite exposure to active drug concentrations determines the efficacy and/or persistence of activity for most of the anthelmintic drugs used in ruminants. The outcome from integrated pharmaco-parasitological research approaches addressed to interpret the host-drug-parasite relationship has greatly contributed to optimise drug activity. The integrated assessment of the drug disposition in the host, the mechanisms of drug influx/efflux in different target helminths, their biotransformation/detoxification capacities and the chemically-induced modulation of those transport/metabolism processes, has signified a relevant progress on the understanding of the pharmacology of anthelmintic drugs in ruminant species. Further pharmaco-parasitological interdisciplinary work, supported by the huge progress achieved on parasite genomics, will be essential to generate the basic scientific knowledge necessary to preserve existing and particularly, novel active ingredients as useful tools for parasite control in livestock animals. The basic and clinical pharmacology issues summarised in the current article contribute in that direction. Keywords: Ruminants, anthelmintic drugs, pharmaco-parasitological assessment of drug activity

Helminths are responsible for numerous health problems in both animals and human around the world. In animals, they cause heavy losses in meat, milk and wool production. The only available mean for controlling the resulting diseases are currently treatments with anthelmintics. Unfortunately, many cases of drug resistance have emerged affecting most of the antiparasitic compounds. While attempts are made for finding new groups of drugs, efforts are also made for understanding the underlying mechanisms of drug resistance or reduced efficacy of anthelmintics. Among the mechanisms, the identification of alterations in drug transport, specifically in active transport due to protein transporters, has been the aim of several recent investigations. Mechanisms very similar to those responsible for failures in cancer therapy have been described. Many progresses in genomic analyses have been made, especially thanks to the model nematode Caenorhabditis elegans. A better knowledge of the role of these transporters in the efficacy of anthelmintics should conduct to the development of new strategies in antiparasitic therapy and the identification of effective and non-toxic inhibitors of the efflux pumps of helminths. Keywords: Helminths, nematodes, trematodes, drug transport, p-glycoprotein, lipids

A major concern for helminth parasite control in human and animal health is the development of anthelmintic resistance. The mutations that lead to such resistance do so in several ways including, loss of drug binding, modification of response once the drug has bound and loss of the drug target altogether. Benzimidazole resistance is best characterized by amino acid substitutions at three positions of the beta-tubulin protein: F167Y, E198A and F200Y, each of which causes loss of drug binding. Macrocyclic lactone resistance has been linked in the laboratory to mutations in different ligand-gated chloride-channel subunit genes, Hco-glc-5, Hco-lgc-37 and Con-avr-14 with substitutions A159V, K159R and L256F. These alter the channel response to drug binding, reducing its effects, which can also be seen in vivo. Levamisole resistance, including pyrantel and other related compounds, has been more difficult to characterize. More recently, loss of specific acetylcholine gated ion-channels that are targeted by the drug has been demonstrated with functional and molecular evidence. The loss of specific ion-channel targets of both the macrocyclic lactones and the new monepantel also seems to be a more general mechanism of anthelmintic resistance that requires further study. Praziquantel resistance is associated with SNPs in the β subunit forming voltage-gated Ca2+ channels. By placing our knowledge of the characteristics of these mutations in a framework of their biochemistry, functional characteristics, population genetics and effects in vivo gives us a more comprehensive understanding of how these mutations behave. This in turn should ultimately help us to minimize their impact.

Anthelmintic resistance in humans has been suspected but remains until now anecdotic compared to the extension of the phenomenon in helminths of livestock or Plasmodium in humans. Human mass drug treatment has been offered against several filarial diseases, schistosomiasis and soil-transmitted nematode infections, thus the appearance of resistance is expected. Up to now the used drugs remain active but a follow up of their efficacy is needed. A poor observed efficacy is not always due to resistance and cases of false resistance are recorded or suspected. In such cases, the quality of the drug may be faulty since many of the proposed drugs on shelf are counterfeit in poor countries; in other countries the unregulated internet pharmacies may also propose counterfeit drugs. The quality drug may also have a poor absorption or metabolisation due to diet or to concomitant treatments of the patients. False resistance observation may arise from poor diagnostic or misdiagnosis and then diagnostic improvement is the main solution to be proposed. The evaluations of resistance in the field are mostly derived from in vivo efficacy assessments based in majority on before and after treatment measurements. The use of control group when feasible and more refined statistical tools should be implemented. When the resistance mechanisms are partly known (several classes of drugs in malaria or benzimidazole resistance of nematodes) molecular tests on parasites would be the best instrument for a follow up of resistance. The last cause of false resistance could also be simply poor compliance of drug use, particularly when the drug exerts unpleasant side effects or when the duration of treatment is long. The assessment of resistance is not always easy in field conditions due to all these confounding effects and false resistance should be an issue to be considered in most cases. Keywords: False resistance, counterfeit drug, efficacy test, compliance, anthelmintic, malaria, nematode, schistosoma

Helminth parasitic diseases are mainly controlled by anthelmintic treatments, but control schemes are now threatened by the large development of anthelmintic resistance. Integrated parasite management needs to be developed but processes underpinning parasite population dynamics and resistant gene evolution are still lacking. Here, we review the mathematical models that have been developed to understand the evolution of anthelmintic resistance in host-helminth parasite models (intestinal helminth parasites of herbivores and human soil-transmitted helminths). A first part is dedicated to generic models that allowed the understanding of processes underlying host-helminth parasite models: the identification of factors responsible for epidemiological patterns observed (i.e. persistence, aggregated distribution, density-dependence regulations) and the consequences of these factors on resistance gene evolution. In a second part, we review mathematical models developed to investigate alternative management strategies, based on a rational use of anthelmintics with the aim of both controlling parasite infection and maintaining resistance gene frequency at low levels. As a conclusion, key factors that should be incorporated in mathematical models to investigate the efficiency of management strategies are discussed.