Antechodynamics and Antechokinetics: Dynamics and Kinetics of Antibiotic Resistance Biomolecules

Abstract

The pharmacology of antimicrobial agents comprises pharmacodynamics and pharmacokinetics. Pharmacodynamics refers to studying drugs' mode of action on their molecular targets at various concentrations and the resulting effect(s). Pharmacokinetics refers to studying the way(s) in which drugs enter the body and are distributed to their targets in various compartments (such as tissues) and how local drug concentrations are modified in time, such as by metabolism or excretion. Pharmacodynamics and pharmacokinetics constitute pivotal knowledge for establishing the breakpoints used to identify the appropriate antimicrobial agents for infection therapy. Antibiotic resistance is the biological force opposing antimicrobials' pharmacological effects. However, we do not have a term similar to pharmacology for microbial antibiotic resistance reactions. Here, we propose the new scientific field of antechology (from the classic Greek antechó, resistance), studying the dynamics and kinetics of antibiotic resistance molecules which oppose the effect of antimicrobial drugs. Antechodynamics refers to the study of the molecular mechanisms through which antibiotic molecules are chemically modified or degraded by particular bacterial resistance enzymes (primary effectors) or drive the modification of an antibiotic's target inhibition sites through molecules released by antibiotic action on the microorganism (secondary effectors). Antechokinetics refers to the study of the processes leading to bacterial spatial cellular (subcellular, pericellular, extracellular) localizations of the molecules involved in antibiotic detoxifying mechanisms. Molecules' local concentrations change over time due to their production, their degradation, and ultimately their excretion rates. We will examine the antechodynamics and antechokinetics for various antimicrobial classes and the relation between pharmacodynamics/pharmacokinetics and antechodynamics/antechokinetics.

Keywords: antechodynamics; antechokinetics; antechology; antibiotic resistance; antibiotics; pharmacodynamics; pharmacokinetics.

Figure 1

Antibiotic actions and resistance reactions. Blue circles = antibiotic targets; when disturbed (dark green arrows), the result is bacterial extinction or growth inhibition. The biomolecules involved in resistance counteract antibiotics’ action (red arrows), destroying or altering the antibiotic (blast) through antechodynamic primary (1) effectors or secondary (2) effectors that act by triggering the primary effectors, preventing antibiotic–target binding (red squares), or pumping out the antibiotic (cylinder), as a result of the antibiotic’s action on a target. The result is bacterial cell survival or growth. Antibiotic pharmacology predicts antibiotics’ effectiveness; antechology predicts antibiotic resistance.

Figure 2

A schema of the antechodynamic and antechokinetic processes in a bacterial cell. Blue double circles represent antibiotic targets. The dotted frame represents the bacterial ribosomes, mainly located in the region below the cytoplasmic membrane; the gray double ovals are a magnification of the ribosomes (see magnifying glasses). Green arrows represent antibiotics entering and eventually being detoxified, either destroyed; structurally modified to prevent binding to the target; or pumped out (red crosses). Antechodynamic primary effector biomolecules (red lines) directly target (often destroying or modifying) the antibiotic. Antechodynamic secondary effectors (yellow lines) are biomolecules resulting from antibiotic action that activate the primary effectors or modify the antibiotic target, preventing drug binding. The intracellular spatial trajectories of the detoxifying molecules (red and yellow lines), such as their relative abundance in relation to the target density and their stability within the cell, are much less understood; this is the field of antechokinetics. See the text for more detailed information.