Abstract
The new era of multidrug resistance of pathogens against frontline antibiotics has compromised the immense therapeutic gains of the ‘golden age,’ stimulating a resurgence in antimicrobial research focused on antimicrobial and immunomodulatory components of botanical, fungal or microbial origin. While much valuable information has been amassed on the potency of crude extracts and, indeed, purified compounds there are too many reports that uncritically extrapolate observed in vitro activity to presumed ingestive and/or topical therapeutic value, particularly in the discipline of ethnopharmacology. Thus, natural product researchers would benefit from a basic pharmacokinetic and pharmacodynamic understanding. Furthermore, therapeutic success of complex mixtures or single components derived therefrom is not always proportionate to their MIC values, since immunomodulation can be the dominant mechanism of action. Researchers often fail to acknowledge this, particularly when ‘null’ activity is observed. In this review we introduce the most up to date theories of oral and topical bioavailability including the metabolic processes affecting xenobiotic biotransformation before and after drugs reach the site of their action in the body. We briefly examine the common methodologies employed in antimicrobial, immunomodulatory and pharmacokinetic research. Importantly, we emphasize the contribution of synergies and/or antagonisms in complex mixtures as they affect absorptive processes in the body and sometimes potentiate activity. Strictly in the context of natural product research, it is important to acknowledge the potential for chemotypic variation within important medicinal plants. Furthermore, polar head space and rotatable bonds give a priori indications of the likelihood of bioavailability of active metabolites. Considering this and other relatively simple chemical insights, we hope to provide the basis for a more rigorous scientific assessment, enabling researchers to predict the likelihood that observed in vitro anti-infective activity will translate to in vivo outcomes in a therapeutic context. We give worked examples of tentative pharmacokinetic assessment of some well-known medicinal plants.
Highlights
THE ‘DARK AGE’ OF ANTIBIOTICSThe pharmacotherapeutic value of antimicrobial and immunomodulatory drugs critically depends on the orchestration of properties influencing pharmacokinetics and pharmacodynamics
Characteristics influencing pharmacokinetic fate of a specific drug critically depend on its chemical functional groups, which are the basis for a priori insight into the possibility of absorption or transdermal penetration
It could be argued that the modern techniques of molecular docking and rational drug design have demonstrated little success by comparison with the much less sophisticated screening methods employed during the ‘golden era’ of antibiotic discovery and this gives impetus to calls for a new iteration of natural product screening in the search for new efficacious drugs and novel drug scaffolds (Lyddiard et al, 2016)
Summary
The pharmacotherapeutic value of antimicrobial and immunomodulatory (anti-infective) drugs critically depends on the orchestration of properties influencing pharmacokinetics and pharmacodynamics. The preliminary steps taken before measuring biological activity should involve tentative interpretation in the context of pharmacokinetics by closer examination of polar functional groups known to influence absorption and the number of rotatable bonds This is critical when therapies are ingested and expected to act non-locally (not in the digestive tract) and require sufficiently high systemic concentration. It could be argued that the modern techniques of molecular docking and rational drug design have demonstrated little success by comparison with the much less sophisticated screening methods employed during the ‘golden era’ of antibiotic discovery and this gives impetus to calls for a new iteration of natural product screening in the search for new efficacious drugs and novel drug scaffolds (Lyddiard et al, 2016) Another lesson we could learn from the ‘dark age,’ and Fleming’s grim yet accurate prediction, is to direct research efforts toward development of combination therapy drugs, by contrast with the monotherapy drug approach that ushered in the resistance paradigm (Cock, 2018). This new paradigm of dual-therapy drugs opens a potential niche for the common non-specific antimicrobials found in natural product research that could be used to complement the conventional antibiotics that are losing potency in the unrelenting march of microbial resistance
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