Physical Insights into Permeation of and Resistance to Antibiotics in Bacteria

Abstract

Bacteria can resist antibiotics simply by hindering physical access to the interior, where in general antibiotic targets are located. Gram-negative bacteria, protected by the outer membrane, possess in the latter several porins that act as a gate for the exchange of small hydrophilic molecules. These porins are water-filled membrane-protein channels that are considered to be the main pathway for different class of antibiotics, such as beta-lactams and fluoroquinolones. Bacterial strains resistant to antibiotics can either decrease the density of porins expressed in the outer membrane or decrease the porin internal size by mutating a few amino acids. In both cases, understanding how antibiotics diffuse through bacterial porins can help the design of new antibiotics that have better penetrating power. A considerable contribution can be offered by molecular dynamics simulations since reliability of force fields, computer power, and algorithms have considerably increased the predictive power thereof. Large systems, as pores inserted in a membrane, and long simulation runs are now feasible, and the time scale can be even extended via the use of accelerated techniques, such as metadynamics, and combined strategies. The details of interactions and processes, extracted from the simulations, complement experimental findings and also deepen aspects not accessible to experiments. In this paper we will review the results obtained by our group on this topic with a particular focus on possible general criteria that can guide the rational design of new antibacterial compounds.

Tricyclic GyrB/ParE (TriBE) Inhibitors: A New Class of Broad-Spectrum Dual-Targeting Antibacterial Agents

“…Diamine substituents at R 4 like the (3aR,6aR)-octahydropyrrolo[3,4- b ]pyrrole used in C3 were observed to significantly enhance Gram-negative antibacterial activity and spectrum by improving both enzyme inhibitor potency and imparting physicochemical characteristics to inhibitors that addressed the unique characteristics of the Gram-negative cell envelope. Drug efflux pumps and the orthogonal sieving properties of the inner and outer membranes of the Gram-negative cell envelope pose significant barriers to the development of antibacterial agents that need access to cytoplasmic targets; the outer membrane is selectively permeable to small charged or polar molecules via porins, while the inner membrane lipid bilayer is essentially impermeable to charged ions, but contains efflux pumps that actively transport lipophilic molecules out of the cell [19,20]. Fluoroquinolones and tetracyclines, which are active against Gram-negative bacteria, equilibrate between neutral (minor) and charged (predominant) states at physiological pH [20].…”

Structure, Function and Regulation of Outer Membrane Proteins Involved in Drug Transport in Enterobactericeae: the OmpF/C – TolC Case

“…The electrophysiological studies of porins have been largely discussed in recent reviews [3,9,10]. Briefly, the method consists in the reconstitution of purified proteins into planar lipid bilayers; ion-current measurements provide structural and functional characteristics such as conductance (e.g.…”

“…The prevalence of these strategies in MDR clinical isolates highlights the importance to understand the molecular bases of the antibiotic influx mechanism. In particular, advances in molecular modeling approaches are promising to study subtle porin-antibiotic interactions [10, 11]. Such information could used to screen for antibiotics with enhanced diffusion properties through porins.…”

Molecular Dynamics Computer Simulations of Multidrug RND Efflux Pumps

“…With old antibiotics losing their efficiency faster than new ones can be developed [38], a detailed understanding of the molecular basis of microbial multi-drug resistance is paramount for modern biomedical research. The main mechanisms of action underlying antibiotics resistance include the alteration of the drug, the alteration of the drug target as well the reduction of antibiotics concentration inside the bacterium by lowering influx into and/or enhancing the extrusion out of the organism [39, 40]. …”