Recent Trends in Synthesis of Chloramphenicol New Derivatives

Chloramphenicol (CAM), the bacteriostatic broad-spectrum antibiotic, isolated from Streptomyces venezuelae during the “golden era” of antibiotic discovery, nowadays has limited clinical potential due to adverse side effects and frequent antimicrobial resistance. Numerous CAM analogs were synthesized in order to find the derivatives with improved pharmacological properties and activity on resistant bacterial strains. This work aims to summarize the most recent achievements in obtaining new CAM analogs reported during the last five years. Current investigations are mainly focused on elucidating the molecular basis of the mode of CAM action and determining the mechanisms of resistance to this class of antibiotics or on studies of the possible use of the CAM scaffold to search for therapeutic agents with different CAM modes of action—such as selective antiproliferative agents or bacterial cell wall biosynthesis inhibitors. Hopefully, a deeper understanding of the CAM interactions with the target and its specificity will generate research ideas for developing new effective drugs

Pore-forming activity of new conjugate antibiotics based on amphotericin B

<div><p>A series of amides of the antifungal antibiotic amphotericin B (AmB) and its conjugates with benzoxaboroles was tested to determine whether they form pores in lipid bilayers and to compare their channel characteristics. The tested derivatives produced pores of larger amplitude and shorter lifetime than those of the parent antibiotic. The pore conductance was related to changes in the partial charge of the hydrogens of the hydroxyl groups in the lactone ring that determined the anion coordination in the channel. Neutralization of one of the polar group charges in the AmB head during chemical modification produced a pronounced effect by diminishing the dwell time of the polyene channel compared to modification of both groups. In this study, compounds that had a modification of one carboxyl or amino group were less effective in initializing phase separation in POPC-membranes compared to derivatives that had modifications of both polar groups as well as the parent antibiotic. The effects were attributed to the restriction of the aggregation process by electrical repulsion between charged derivatives in contrast to neutral compounds. The significant correlation between the ability of derivatives to increase the permeability of model membranes—causing the appearance of single channels in lipid bilayers or inducing calcein leakage from unilamellar vesicles—and the minimal inhibitory concentration indicated that the antifungal effect of the conjugates was due to pore formation in the membranes of target cells.</p></div

Time dependence of relative fluorescence of calcein (<i>IF</i>, %) leaked from POPC:Erg (67:33 mol %) vesicles.

<p>The moment of addition of AmB (<b><i>1</i></b>) or its conjugates (<b><i>2</i></b> ÷ <b><i>10</i></b>) into a liposomal suspension up to 50 μM is indicated by an arrow.</p

Current fluctuations corresponding to openings and closures of single channels induced by AmB (<i>1</i>) and compounds ## 1305 (<i>2</i>), 1394 (<i>3</i>), 2451(<i>4</i>), 2255 (<i>5</i>), 2410 (<i>6</i>), 2411 (<i>7</i>), 2440 (<i>8</i>), 2444 (<i>9</i>), and 2481 (<i>10</i>).

<p>The lipid bilayers compared to DPhPC:Erg (67:33 mol %) and bathed in 2.0 M KCl (pH 7.4). The transmembrane voltage was –150 mV.</p

Characteristic parameters of the membrane activity of AmB (<i>1</i>) and its conjugates (<i>2</i>–<i>10</i>).

<p>Characteristic parameters of the membrane activity of AmB (<i>1</i>) and its conjugates (<i>2</i>–<i>10</i>).</p

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<p><b>Dependence of DNA binding affinity of compounds 1 (A) and 3 (B) on the ionic strength of solution.</b> DNA binding constants of <b>1</b> and <b>3</b> obtained in solutions that contained 5mM MgCl₂ (filled circles) and no MgCl₂ (open circles). Linear approximations shown by solid lines with the slope SK = ∂logK/∂log[KCl].</p

Synthesis and evaluation of biological activity for dual-acting antibiotics on the basis of azithromycin and glycopeptides

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Discrimination between G/C Binding Sites by Olivomycin A Is Determined by Kinetics of the Drug-DNA Interaction

Olivomycin A (OA) exerts its cytotoxic potency due to binding to the minor groove of the G/C-rich DNA and interfering with replication and transcription. Screening of the complete set of tetranucleotide G/C sites by electrophoretic mobility gel shift assay (EMSA) revealed that the sites containing central GC or GG dinucleotides were able to bind OA, whereas the sites with the central CG dinucleotide were not. However, studies of equilibrium OA binding in solution by fluorescence, circular dichroism and isothermal titration calorimetry failed to confirm the sequence preference of OA, indicating instead a similar type of complex and comparable affinity of OA to all G/C binding sites. This discrepancy was resolved by kinetics analysis of the drug&ndash;DNA interaction: the dissociation rate significantly differed between SGCS, SGGS and SCGS sites (S stands for G or C), thereby explaining the disintegration of the complexes during EMSA. The functional relevance of the revealed differential kinetics of OA&ndash;DNA interaction was demonstrated in an in vitro transcription assay. These findings emphasize the crucial role of kinetics in the mechanism of OA action and provide an important approach to the screening of new drug candidates

Binding of compounds 1–3 to the pUC19 plasmid DNA monitored by electrophoretic mobility in 1% agarose gel.

<p>The plasmid was incubated with the compounds at indicated concentrations (μM) in BB-Mg buffer containing 5 mM MgCl₂ (A) or BB buffer (same buffer with no MgCl₂) (B). Migration of the free compound is shown at the highest concentration (25 μM) for each drug (arrows). Bottom panels in A and B: electrophoresis with EtBr in the gel and in the running buffer.</p