Frontiers in Anti-Infective Drug Discovery

Antimicrobial drug development over the last two decades suggests that the choice of dose and dosing regimen can be selected at a very early stage. This is achieved by optimizing several key factors that are properties of the drug, the bug, and the host species. Drug exposure metrics, relative to the potency of the drug, are computed during the early stages of anti-infective drug development. These metrics serve as predictors of efficacy in the animal models of infection. Drug exposure relative to its potency can be expressed using a few metrics such as AUC/MIC, T>MIC, or Cmax/MIC. The class of drugs that the anti-infective belongs to often determines the optimal choice of the metric for a given anti-microbial (and is empirically chosen based on pre-clinical data). There are various anti-microbial drug classes available on the market. Despite a large number of drug classes, there is reasonable consensus that the PK/PD target, i.e. metric of relative drug exposure described above, obtained from in vitro and animal experiments can predict the efficacy of specific drugs in humans. The steps involved in the derivation of this crucial PK/PD metric and dosing regimen in humans are as follows: (a) First, the metric is chosen and then the magnitude of the metric is computed using in vitro and animal PK/PD experiments; (b) Next, drug properties such as plasma protein binding are included as correction factors for the PK/PD target; (c) Finally, the non-clinical information is combined with early clinical pharmacokinetic data to estimate which dosing regimen has the greatest probability of attaining the PK/PD metric. This methodology of computing the dosing regimen and estimating the probability of successful target attainment accounts for two key sources of variability. These are between-patient variation in clinical pharmacokinetics and the gamut of MIC values that reflect the susceptibility of pathogens to the anti-microbial drug. These sources of variability are incorporated by running Monte Carlo simulations that are populationbased in nature i.e. they account for variability in both the pathogen and the host. These sophisticated simulations answer the critical question around the rate of target attainment for dosing regimens of the new antibiotic drug. In summary, combining invitro data, animal PK/PD, early clinical pharmacokinetics, and Monte Carlo simulations expedites decision making in antimicrobial drug development. These efficiencies can lead to earlier and faster entry into full development for anti-microbials and aid optimal choice of dose regimen for phase 2/3 studies.

Post-translational modifications are changes introduced to proteins after their translation. They are the means to generate molecular diversity, expand protein function, control catalytic activity and trigger quick responses to a wide range of stimuli. Moreover, they regulate numerous biological processes, including pathogen invasion and host defence mechanisms. It is well established that bacteria and viruses utilize post-translational modifications on their own or their host’s proteins to advance their pathogenicity. Doing so, they evade immune responses, target signaling pathways and manipulate host cytoskeleton to achieve survival, replication and propagation. Many bacterial species secrete virulence factors into the host and mediate hostpathogen interactions by inducing post-translational modifications that subvert fundamental cellular processes. Viral pathogens also utilize post translational modifications in order to overcome the host defence mechanisms and hijack its cellular machinery for their replication and propagation. For example, many coronavirus proteins are modified to achieve host invasion, evasion of immune responses and utilization of the host translational machinery. PTMs are also considered potential targets for the development of novel therapeutics from natural products with antibiotic properties, like lasso peptides and lantibiotics. The last decade, significant progress was made in understanding the mechanisms that govern PTMs and mediate regulation of protein structure and function. This urges the identification of relevant molecular targets, the design of specific drugs and the discovery of PTM-based medicine. Therefore, PTMs emerge as a highly promising field for the investigation and discovery of new therapeutics for many infectious diseases.

Antimicrobial resistance of Gram-negative bacteria is a major concern, and no new classes of antibiotics that are effective against this type of bacteria have been discovered since the 1960s. During the last decades, multiple approaches have been developed to combat such bacterial resistance. However, the combination of antibiotic resistance mechanisms by bacteria and the limited number of effective antibiotics available, decreases the number of interventions for the treatment of current bacterial infections. The solution to emerging antibiotic resistance will likely involve new therapies or new classes of antibacterial agents. For a few years now, there was a real interest in the design and synthesis of hydrazones possessing an azometine -NHN=CHproton and constituting an important class of compounds for new drugs development as anticonvulsants, antidepressants, antitumoral agents. In this context, the design and antimicrobial evaluation of hydrazone derivatives have constituted one of the new strategies developed to fight bacterial resistance. As pointed out, the range of biological activities is very broad, and this review will deal exclusively with the synthesis and use of hydrazones as antimicrobial agents and will not cover the other biological properties already well depicted in literature. Thus, we will report herein the scope and limitation of such an approach providing numerous examples demonstrating structure-activity relationships and potent interesting antimicrobial activities against both fungi, Grampositive and/or Gram-negative bacteria.

Leishmaniasis is a neglected tropical disease caused by a protozoan parasite of the genus Leishmania, mainly associated with the lack of community hygiene and poverty in the developing countries. Leishmaniasis can be cured but the emergence of drug resistance makes it difficult to completely eradicate the disease. Even after so many years, there is still no vaccine available against leishmaniasis. Therefore, treatment of the disease is mainly dependent on the available therapeutic drugs. However, the current chemotherapeutic drugs have several drawbacks such as high toxicity, less efficacy, high cost and emergence of drug resistance, etc. So, to boost the elimination of disease, development of newer therapeutic agents is imperative. As all this is very well-known, including the current anti-leishmanial drugs with their adverse effects, the authors state that the main objective of this book chapter is to present an overview of the disease, its different clinical forms and the diagnostic tools available for the detection of the disease. Natural sources such as plants and microorganisms have shown great results against Leishmania species over the years, indicating that they may be considered as therapeutic agents. Hereafter, potent investigational drugs obtained from the natural sources such as medicinal plants and microorganisms are also discussed in this book chapter.

Dengue is the most significant arthropod-borne viral infection of humans. More than 3.8 billion people live in endemic areas. Dengue virus infection (DVI) results in more than 500,000 hospitalizations every year, with increased threats of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) during secondary infections. In spite of the high disease burden of the dengue virus, there are no specific antiviral drugs available, and the approved vaccine is harmful in the naïve population with respect to the initiation of primary dengue infection. Several clinically approved drugs have entered human clinical trials. This review addresses the repurposing drug targets that have been investigated in DHF and DSS patients. Furthermore, their essential antiviral action and specific classes of clinically approved drugs have been clarified. These clinical trials' outcomes can enhance our understanding of the antiviral activities of these repurposing drugs to alleviate the clinical severity of dengue viral infection.