Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

Activitat antibiòtica; Ribosoma bacterià; Simulacions de dinàmica molecularActividad antibiótica; Ribosoma bacteriano; Simulaciones de dinámica molecularAntibiotic activity; Bacterial ribosome; Molecular dynamics simulationsIn the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.This research was funded by RFBR [grants 20-04-00873 to N.V.S. (synthesis of analogs, binding assays, in vitro translation), 20-015-00537 to P.A.N. (potential measurement, screening of TolC-containing transporters), and 20-54-76002 to I.A.O. (toeprinting and in vitro translation)], President grant MD 2626.2021.1.4 to I.A.O. (bacteria inhibition assays), grants from the Instituto de Salud Carlos III: PI17/02087 to A.L. (cancer cell proliferation assays) by the Ministry of Science and Higher Education of the Russian Federation [grant FENU-2020-0019 to G.I.M. (molecular dynamics simulations)] and by the Government of the Russian Federation [No. AAAA-A17-117120570004-6 to A.A.B.]

Mathematical model of Scheduler with Semi-Markov input and bandwidth sharing discipline

In this paper, we consider single server queueing system with multiple semi-Markov inputs and buffers. Each request of the flows brings to the system some random amount of information. According to the bandwidth sharing discipline, each buffer has its own part of the throughput and the server transmits the information from buffers simultaneously. The aim of the current research is to derive the probability distribution of the amount of information in single buffer

Semi-Markov resource flow as a bit-level model of traffic

In this paper, we consider semi-Markov flow as a bit-level model of traffic. Each request of the flow brings some arbitrary distributed amount of information to the system. The current paper aims to investigate the amount of information received in semi-Markov flow during time unit. We use the asymptotic analysis method under the limit condition of growing time of observation to derive the limiting probability distribution of the amount of information received in the flow and build the approximation of its prelimit distribution function

Manin matrices and Talalaev's formula

We study special class of matrices with noncommutative entries and demonstrate their various applications in integrable systems theory. They appeared in Yu. Manin's works in 87-92 as linear homomorphisms between polynomial rings; more explicitly they read: 1) elements in the same column commute; 2) commutators of the cross terms are equal: $[M_{ij}, M_{kl}]=[M_{kj}, M_{il}]$ (e.g. $[M_{11}, M_{22}]=[M_{21}, M_{12}]$). We claim that such matrices behave almost as well as matrices with commutative elements. Namely theorems of linear algebra (e.g., a natural definition of the determinant, the Cayley-Hamilton theorem, the Newton identities and so on and so forth) holds true for them. On the other hand, we remark that such matrices are somewhat ubiquitous in the theory of quantum integrability. For instance, Manin matrices (and their q-analogs) include matrices satisfying the Yang-Baxter relation "RTT=TTR" and the so--called Cartier-Foata matrices. Also, they enter Talalaev's hep-th/0404153 remarkable formulas: $det(\partial_z-L_{Gaudin}(z))$, det(1-e^{-\p}T_{Yangian}(z)) for the "quantum spectral curve", etc. We show that theorems of linear algebra, after being established for such matrices, have various applications to quantum integrable systems and Lie algebras, e.g in the construction of new generators in $Z(U(\hat{gl_n}))$ (and, in general, in the construction of quantum conservation laws), in the Knizhnik-Zamolodchikov equation, and in the problem of Wick ordering. We also discuss applications to the separation of variables problem, new Capelli identities and the Langlands correspondence.Comment: 40 pages, V2: exposition reorganized, some proofs added, misprints e.g. in Newton id-s fixed, normal ordering convention turned to standard one, refs. adde

MDR Pumps as Crossroads of Resistance: Antibiotics and Bacteriophages

At present, antibiotic resistance represents a global problem in modern medicine. In the near future, humanity may face a situation where medicine will be powerless against resistant bacteria and a post-antibiotic era will come. The development of new antibiotics is either very expensive or ineffective due to rapidly developing bacterial resistance. The need to develop alternative approaches to the treatment of bacterial infections, such as phage therapy, is beyond doubt. The cornerstone of bacterial defense against antibiotics are multidrug resistance (MDR) pumps, which are involved in antibiotic resistance, toxin export, biofilm, and persister cell formation. MDR pumps are the primary non-specific defense of bacteria against antibiotics, while drug target modification, drug inactivation, target switching, and target sequestration are the second, specific line of their defense. All bacteria have MDR pumps, and bacteriophages have evolved along with them and use the bacteria’s need for MDR pumps to bind and penetrate into bacterial cells. The study and understanding of the mechanisms of the pumps and their contribution to the overall resistance and to the sensitivity to bacteriophages will allow us to either seriously delay the onset of the post-antibiotic era or even prevent it altogether due to phage-antibiotic synergy

Antimicrobial Action Mechanisms of Natural Compounds Isolated from Endophytic Microorganisms

Infectious diseases are a significant challenge to global healthcare, especially in the face of increasing antibiotic resistance. This urgent issue requires the continuous exploration and development of new antimicrobial drugs. In this regard, the secondary metabolites derived from endophytic microorganisms stand out as promising sources for finding antimicrobials. Endophytic microorganisms, residing within the internal tissues of plants, have demonstrated the capacity to produce diverse bioactive compounds with substantial pharmacological potential. Therefore, numerous new antimicrobial compounds have been isolated from endophytes, particularly from endophytic fungi and actinomycetes. However, only a limited number of these compounds have been subjected to comprehensive studies regarding their mechanisms of action against bacterial cells. Furthermore, the investigation of their effects on antibiotic-resistant bacteria and the identification of biosynthetic gene clusters responsible for synthesizing these secondary metabolites have been conducted for only a subset of these promising compounds. Through a comprehensive analysis of current research findings, this review describes the mechanisms of action of antimicrobial drugs and secondary metabolites isolated from endophytes, antibacterial activities of the natural compounds derived from endophytes against antibiotic-resistant bacteria, and biosynthetic gene clusters of endophytic fungi responsible for the synthesis of bioactive secondary metabolites.</p

Spiro-condensation of 5-methoxycarbonyl-1Hpyrrole-2,3-diones with cyclic enoles to form spiro substituted furo[3,2-c]-coumarins and quinolines

Highly efficient spiro-condensation enabling cyclic enoles to act as 1,3-bis-nucleophiles in reaction with pyrrole-2,3-diones acting as 1,2-bis-electrophiles was developed. The corresponding furo[3,2-c]coumarins and furo[3,2-c]quinolines containing a spiro pyrrole fragment were obtained in high yields

Multi-level MMPP as a model of fractal traffic

In this paper, we propose the multi-level Markov modulated Poisson process with arbitrary distribution of the packet length as a model of fractal traffic. For the total amount of information received in multi-level MMPP, we investigate the probability distribution and present the algorithm of calculating the first and the second moments. Using asymptotic analysis method, we build Gaussian approximation of aforementioned distribution. We show that the convergence time of the probability distribution to the Gaussian distribution forms the period where the Hurst parameter is stable and reflects the self-similarity of the multi-level MMPP

Analysis of the amount of information in semi-Markov flow

In this paper, we consider semi-Markov flow as a model of bit-level traffic. Each request of the flow brings some arbitrary distributed amount of information. The current paper aims to investigate the amount of information received in semiMarkov flow. We use the asymptotic analysis method under the limit condition of growing time of observation to derive the limiting probability distribution of the amount of information received in the flow and build its approximation