Tuberculosis: An Overview of the Immunogenic Response, Disease Progression, and Medicinal Chemistry Efforts in the Last Decade toward the Development of Potential Drugs for Extensively Drug-Resistant Tuberculosis Strains.

Tuberculosis (TB) is a slow growing, potentially debilitating disease that has plagued humanity for centuries and has claimed numerous lives across the globe. Concerted efforts by researchers have culminated in the development of various strategies to combat this malady. This review aims to raise awareness of the rapidly increasing incidences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, highlighting the significant modifications that were introduced in the TB treatment regimen over the past decade. A description of the role of pathogen-host immune mechanisms together with strategies for prevention of the disease is discussed. The struggle to develop novel drug therapies has continued in an effort to reduce the treatment duration, improve patient compliance and outcomes, and circumvent TB resistance mechanisms. Herein, we give an overview of the extensive medicinal chemistry efforts made during the past decade toward the discovery of new chemotypes, which are potentially active against TB-resistant strains.

Ultraselective antibiotic sensing with complementary strand DNA assisted aptamer/MoS2 field-effect transistors.

Although aptamer has been demonstrated as an important probe for antibiotic determination, the selective sensing of different antibiotics is still a challenge due to their structure similarities and wide folding degrees of aptamer. Herein, a field-effect transistor using MoS2 nanosheet as the channel and an aptamer DNA (APT) with its configuration shaped by a complementary strand DNA (CS) is employed for kanamycin (KAN) determination. This probe structure contributes to an enhanced selectivity and reliability with reduced device-to-device variations. This MoS2/APT/CS sensor shows time-dependent performance in antibiotic sensing. Prolonged detection time (20 s-300 s) leads to an enhanced sensitivity (1.85-4.43 M-1) and a lower limit of detection (1.06-0.66 nM), while a shorter detection time leads to a broader linear working range. A new sensing mechanism relying on charge release from probe is proposed, which is based on the "replacement reaction" between KAN and APT-CS. This sensor exhibits an extremely high selectivity (selectivity coefficient of 12.8) to kanamycin over other antibiotics including streptomycin, tobramycin, amoxicillin, ciprofloxacin and chloramphenicol. This work demonstrates the merits of probe engineering in label-free antibiotic detection with FET sensor, which presents significant promises in sensitive and selective chemical and biological sensing.

Identification of antibiotic mycelia residues in cottonseed meal using Fourier transform near-infrared microspectroscopic imaging.

Near-infrared microscopy (NIRM) technology can analyze different components within a sample while also obtaining spatial information about the sample. No rapid detection methods are available for effectively identifying antibiotic mycelia residues (AMRs) in protein feeds materials to date. In this study, the feasibility of using NIRM to identify AMRs (oxytetracycline residue, streptomycin sulfate residue and clay colysin sulfate residue) mixed in cottonseed meals was studied. The samples were scanned by NIRM, then the spectra of images were analyzed by principal component analysis (PCA) to select characteristic bands for further identification with one-class partial least squares analysis (OCPLS). The results showed that: a) AMRs were effectively identified in cottonseed meal; b) screening characteristic bands and increasing the spectral number of the calibration set improved the identification results of the model; and c) the sensitivity, specificity, accuracy and class error of the method were 100%, 95.93%, 99.01% and 2.03%, respectively.

Streptomycin hydrazone derivatives: synthesis and molecular recognition in aqueous solution.

Five hydrazone derivatives of streptomycin were synthetized (D0h, D1ph, D2bt, D3dctf, D4ag) and characterized by IR, 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. Protonation constants were determined by potentiometry for all derivatives. D1ph and D2bt derivatives were investigated as receptors of dicarboxylates and adenine nucleotides in aqueous solution by potentiometric and 1H NMR titrations. D1ph and D2bt derivatives have the highest affinity with AMP and ATP, respectively, which shows that electrostatic forces are not always the dominant factor in binding of streptomycin derivatives with nucleotides, but the conformational fit between them. Calculated structures at the DFT level of the D1ph derivative bonded with either AMP or ADP showed that the complexes are stabilized by the formation of multiple interactions with the receptors. The antibiotic activity of the derivatives was explored and compared with native streptomycin.

Hydrophilic interaction chromatography-mass spectrometry for anionic metabolic profiling of urine from antibiotic-treated rats.

Hydrophilic interaction chromatography-mass spectrometry (HILIC-MS) was used for anionic metabolic profiling of urine from antibiotic-treated rats to study microbial-host co-metabolism. Rats were treated with the antibiotics penicillin G and streptomycin sulfate for four or eight days and compared to a control group. Urine samples were collected at day zero, four and eight, and analyzed by HILIC-MS. Multivariate data analysis was applied to the urinary metabolic profiles to identify biochemical variation between the treatment groups. Principal component analysis found a clear distinction between those animals receiving antibiotics and the control animals, with twenty-nine discriminatory compounds of which twenty were down-regulated and nine up-regulated upon treatment. In the treatment group receiving antibiotics for four days, a recovery effect was observed for seven compounds after cessation of antibiotic administration. Thirteen discriminatory compounds could be putatively identified based on their accurate mass, including aconitic acid, benzenediol sulfate, ferulic acid sulfate, hippuric acid, indoxyl sulfate, penicillin G, phenol and vanillin 4-sulfate. The rat urine samples had previously been analyzed by capillary electrophoresis (CE) with MS detection and proton nuclear magnetic resonance ((1)H NMR) spectroscopy. Using CE-MS and (1)H NMR spectroscopy seventeen and twenty-five discriminatory compounds were found, respectively. Both hippuric acid and indoxyl sulfate were detected across all three platforms. Additionally, eight compounds were observed with both HILIC-MS and CE-MS. Overall, HILIC-MS appears to be highly complementary to CE-MS and (1)H NMR spectroscopy, identifying additional compounds that discriminate the urine samples from antibiotic-treated and control rats.

Sulfonamide agents for treatment of Staphylococcus MRSA and MSSA infections of the central nervous system.

For drugs that target the central nervous system (CNS) the penetration of the blood-brain barrier (BBB) is a necessity, whereas for other drugs it is an unwanted side-effect. Infections by Staphylococcus aureus (SA) of the CNS causes brain abscesses and inflammation of the tissue enclosing the brain and spinal cord. In this study four sulfonamide agents are compared to streptomycin for growth inhibition of SA bacteria in vitro. All sulfonamide agents were synthesized using microwave irradiation techniques. All drugs tested show substantial growth inhibition of MRSA and MSSA types of Staphylococcus aureus. Important pharmacological properties of streptomycin and sulfonamide drugs are determined to evaluate the efficacy for CNS targeting in clinical treatment of MSSA and and MRSA infections. Although streptomycin demonstrated considerable inhibition of MSSA and MRSA bacteria, the Log P value of -5.28 and polar surface area (PSA) of 331.4 Angstroms(2) effectively inhibits its penetration into the CNS. The Log BB for streptomycin at -4.756 also indicates a very unlikely candidate to treat SA infections of the CNS. All sulfonamide agents showed significant growth inhibition of MRSA and MSSA while having useful values of Log P and PSA for penetrating the BBB. In addition the Log BB values for each sulfonamide agent indicates these agents will enter the CNS to halt SA infections. The Log BB values for sulfonamide drugs 2, A, B, and C are -1.658, -0.109, -0.109, and -0.243, respectively. Values for Log P were 2.549, 3.27, 3.47, and 2.63, respectively; with PSA values at 137.8 A(2), 40.98 A(2), 40.98 A(2), and 49.36 A(2), respectively. The small size of the sulfonamide agents and other physicochemical properties strongly support the contention they can be effectively applied to treat MRSA and MSSA infections of the brain and spinal cord.

Tuberculosis: drug resistance, fitness, and strategies for global control.

Directly observed standardized short-course chemotherapy (DOTS) regimes are an effective treatment for drug susceptible tuberculosis disease. Surprisingly, DOTS has been reported to reduce the transmission of multi-drug resistant tuberculosis, and standardized short-course chemotherapy regimens with first-line agents have been found to be adequate treatments for some patients with drug resistant tuberculosis, including multi-drug resistance. These paradoxical observations and the apparent heterogeneity in treatment outcome of multi-drug resistant tuberculosis when using standard regimens may be due in part to limitations of in vitro drug susceptibility testing based on unique but mistakenly used techniques in diagnostic mycobacteriology. Experimental data and mathematical models indicate that the fitness cost conferred by a resistance determinant is the single most important parameter which determines the spread of drug resistance. Chromosomal alterations that result in resistance to first-line antituberculosis agents, e.g. isoniazid, rifampicin, streptomycin, may or may not be associated with a fitness cost. Based on work in experimental models and from observations in clinical drug resistant isolates a picture emerges in which, among the various resistance mutations that appear with similar rates, those associated with the least fitness cost are selected in the population.