Este trabalho trata da simulação da propagação de ondas eletromagnéticas (1-D) em meios geológicos de propriedades físicas conhecidas (espessura, condutividade e permissividade elétrica), do registro das ondas EM refletidas (dados sintéticos) para uma antena receptora, e do uso desse registro em algoritmos de inversão e otimização que procuram estimar as propriedades físicas dos meios geológicos. Adotou-se modelos geológicos estratificados de pequena espessura (< 1,2 m) e altas frequências para a onda eletromagnética (800, 1000 e 1200 MHz). A propagação da onda eletromagnética é modelada por meio da resolução das equações de Maxwell no método FDTD. Os métodos de inversão Quasi-Newton e Otimização Ant Colony modificado são aplicados sobre os dados sintéticos para estimar os parâmetros elétricos para cada camada geológica. Ambos os métodos foram aplicados alternadamente para aumentar a precisão e a convergência ao longo da profundidade. Os métodos de inversão foram capazes de estimar simultaneamente duas propriedades eletromagnéticas do modelo geológico: a permissividade elétrica e a condutividade elétrica. Os métodos de inversão alcançaram bons resultados quando executados simultaneamente sobre os dados sintéticos em 3 diferentes frequências. Exemplos de estimativas dos perfis de condutividade e permissividade elétricas unidimensionais são apresentados, com e sem inserção de ruídos nos dados. Os resultados indicam que a combinação dos métodos de inversão (ACO modificado e Quasi-Newton) pode fornecer bons resultados para as estimativas dos parâmetros físicos de meios geológicos e geotécnicos em meios rasos. Além disso, essa combinação de métodos de inversão abre novas perspectivas para o processamento de dados georradar multi-canais. As investigações também mostram que a simulação dos perfis sintéticos por meio do método FDTD pode propagar erros em espessuras maiores de subsolo, devido ao fato de ser um método explícito. / This work deals with simulation of a 1-D electromagnetic wave propagating into a geological structure of known physical properties (thickness, electric conductivity and permittivity), the record of the reflected EM wave (synthetic data), and the use of these records in inversion and optimization algorithms to estimate back the physical properties of the geological structure. A stratified and thin (< 1.2 m) geological structure was initially constructed in order to be scanned by high frequency EM waves (800, 1000, and 1200 MHz). The EM wave propagation is simulated by Maxwell equations through FDTD method. The Quasi-Newton inversion and Ant Colony Optimization methods were applied into synthetic data to estimate original physical parameters of each geological layer. Both methods were applied in order to increase precision and convergence along depth. These methods were able to simultaneously estimate two physical properties of the geological structure: electrical permittivity and conductivity. The methods showed good results when applied simultaneously upon synthetic data of all three frequencies. Electric permittivity and conductivity profiles are shown with and without noise in the data. The results indicate that combined inversion methods can show good results to estimate physical properties of thin geological and geothecnical structures. The combined inversion methods open new perspectives to multichannel GPR data processing. The investigations also show that simulation of synthetic data through FDTD can propagate errors when dealing with thick geological structures, due to the fact that FDTD is an explicit method.

Les traitements actuels dirigés contre le VIH ne sont que partiellement efficaces en raison de l'apparition de mutations qui confèrent au virus une grande capacité de résistance aux antirétroviraux existants. Un moyen d'améliorer la lutte contre le virus consiste par conséquent à trouver de nouvelles stratégies d'inhibition. Le complexe de reverse transcription est une des principales cibles pour le développement de traitement anti-SIDA, il catalyse une étape obligatoire du cycle de réplication du virus. Cependant, l'ensemble des inhibiteurs de la transcriptase inverse sont limités par l'apparition rapide de souches résistances. Dans ce contexte, mes travaux de thèse ont permis de développer des inhibiteurs ciblant spécifiquement la reverse transcriptase (RT) du VIH-1, basée sur des fragments d'anticorps dérivés des anticorps chaînes lourdes de dromadaire appelés VHHs ou encore Nanobodies. Associé à une stratégie de vectorisation non invasive basée sur l'utilisation de peptides vecteurs pénétrants, les Nanobodies ont été délivré efficacement dans les cellules et par conséquent ils présentent tous une forte activité antivirale de l'ordre du nanomolaire. L'étude du mécanisme d'action du Nanobody leader NbRT20 montre qu'il agit en tant qu'inhibiteur conformationnel. Il interagit avec la forme intermédiaire inactive de la RT et empêche la mobilité du sous-domaine thumb requis pour le positionnement correct de la matrice/amorce sur la RT et inhibant l'incorporation des nucléotides dans la chaîne d'ADN naissante déstabilisant l'enzyme dans une conformation inactive, non processive. Pris ensemble, ces résultats montrent que la plate-forme Nanobody peut être très efficace pour générer des intracorps extrêmement puissants et sélectifs pour neutraliser la RT et la réplication virale.Mots clés : HIV-1, RT, Nanobodies, peptide vecteur pénétrant / The rapid emergence of drug-resistant viruses against all approved HIV clinical drugs together with inaccessible latent virus reservoirs and side effects of currently used compounds have limited the potency of existing anti-HIV-1 therapeutics. Therefore, there is a critical need for new safer drugs, active against resistant viral strains. Reverse transcriptase (RT) plays an essential role in the replication of human immunodeficiency virus type 1 (HIV-1) and remains a primary target of anti-HIV-1 drugs. To develop specific HIV inhibitors, we have elaborated a new strategy based on short antibody fragments derived from the unique Heavy-chain antibodies present in Camelidae called Nanobodies that targets RT-activation. The immunization of dromedaries with RT has lead to the isolation of a panel of Nanobodies that tightly bind the two subunits of RT and inhibit its DNA-dependent DNA polymerase activity at nanomolar range. From that screen we have elaborated an intrabody (cell penetrating anti-RT Nanobody) NbRT20 that constitutes a potential interesting anti-HIV compound.We demonstrated that NbRT20 inhibits RT polymerase activity and exhibiting a potent antiviral activity with a subnanomolar IC50. NbRT20 binds the thumb subdomain and restricts its flexibility and mobility resulting in an inactive/non processive dimeric conformation of the enzyme. From a mechanistic point of view, we have showed that NbRT20 is a conformational inhibitor. it prevents proper binding of primer/template and of dNTP and destabilizes the enzyme in an inactive/non processive dimeric conformation.Taken together, these results demonstrated that, the Nanobody platform may be highly effective at generating extremely potent and selective intrabody to neutralize RT and HIV proliferation.Key words: HIV-1, RT, Nanobodies, cell penetrating peptide

Ground penetrating radar (GPR) has been extensively utilized as a highly efficient and non-destructive testing method for infrastructure evaluation, such as highway rebar detection, bridge decks inspection, asphalt pavement monitoring, underground pipe leakage detection, railroad ballast assessment, etc. The focus of this dissertation is to investigate the key techniques to tackle with GPR signal processing from three perspectives: (1) Removing or suppressing the radar clutter signal; (2) Detecting the underground target or the region of interest (RoI) in the GPR image; (3) Imaging the underground target to eliminate or alleviate the feature distortion and reconstructing the shape of the target with good fidelity. In the first part of this dissertation, a low-rank and sparse representation based approach is designed to remove the clutter produced by rough ground surface reflection for impulse radar. In the second part, Hilbert Transform and 2-D Renyi entropy based statistical analysis is explored to improve RoI detection efficiency and to reduce the computational cost for more sophisticated data post-processing. In the third part, a back-projection imaging algorithm is designed for both ground-coupled and air-coupled multistatic GPR configurations. Since the refraction phenomenon at the air-ground interface is considered and the spatial offsets between the transceiver antennas are compensated in this algorithm, the data points collected by receiver antennas in time domain can be accurately mapped back to the spatial domain and the targets can be imaged in the scene space under testing. Experimental results validate that the proposed three-stage cascade signal processing methodologies can improve the performance of GPR system.

Les « cell penetrating peptides » (CPPs) sont des vecteurs peptidiques capables de délivrer diverses molécules (acides nucléiques, protéines, peptides, petites molécules, etc.) à l'intérieur des cellules de mammifères. Notre laboratoire a élaboré le vecteur amphipatique secondaire CADY capable de transporter, indépendamment de toute voie d'endocytose, des molécules thérapeutiques telles que les petits ARN interférents (siRNA). En effet, leur potentiel thérapeutique réside dans leur capacité à inhiber de manière spécifique l'expression de protéines dérégulées dans un cadre pathologique.Le sujet de ma thèse s'est centré sur la caractérisation et l'optimisation des complexes CADY/siRNA. Au cours de mes travaux, nous avons pu mettre en évidence que CADY adoptait une structure en hélice alpha en présence du siRNA ce qui conduit à la formation des nanoparticules. Notre étude a eu pour but d'optimiser la séquence de CADY et de contrôler sa formulation pour permettre le transfert de notre système de vectorisation d'une application in cellulo à une application in vivo. En premier lieu, nous avons mené une étude de relations structure-activité avec six peptides analogues de CADY, en réalisant des mutations sur les résidus tryptophanes (PSF1, PSF2, PSF3 et PSW) et sur la zone initiatrice de l'hélice alpha (PG9, PG16). L'analyse approfondie de ces analogues a permis de confirmer que la limitation du caractère amphipathique et du polymorphisme structural des vecteurs conduisaient à une réduction de l'efficacité d'internalisation. Parmi les 6 analogues, seules les nanoparticules à base de PG9 et PG16 présentent des résultats in cellulo comparables à ceux obtenus avec les nanoparticules CADY/siRNA. A ce jour, la séquence primaire de CADY étant la plus adaptée pour la transfection de siRNA, nous avons établi une procédure de formulation standardisée permettant un autoassemblage CADY/siRNA reproductible et homogène, dont la taille moyenne est de 106 ± 31 nm et l'indice de polydispersité de 0,357 ± 0,053. De plus, nous avons mis en place une procédure d'extrusion/lyophilisation afin de stocker les nanoparticules sous forme de poudre. Celle-ci peut être resuspendue en milieu aqueux sans modifications des propriétés colloïdales des nanoparticules ni de leur capacité de transfection.Dans le but d'améliorer la spécificité tissulaire et la biodisponibilité des nanoparticules CADY/siRNA pour une application in vivo, nous avons greffé des motifs de ciblage (YIGSR-S) et de furtivité (PEG) sur la séquence de CADY. L'ajout de ces deux entités, de natures très différentes, ne modifie que faiblement les caractéristiques physico-chimiques (ex. taille moyenne des complexes) et biologiques (transfection cellulaire) des nanoparticules. Ces résultats sont très encourageants pour le développement de nanoparticules dites de 3ème génération, sur lesquelles on peut greffer plusieurs sortes de molécules d'intérêts (ciblage, polymère, agent de contraste etc.).L'ensemble des résultats obtenus au cours de ma thèse marque un réel progrès dans l'optimisation de la formulation du vecteur CADY, et nous incitent à exploiter davantage son potentiel pour le transfert de siRNA in vivo. / Cell penetrating peptides (CPPs) are short peptides that can enter many cell types and transduce into cells a wide range of molecular therapeutics (nucleic acid, proteins, peptides, small molecules, etc.). Our laboratory has developed the secondary amphipathic peptide CADY able to promote the transport of small interfering RNA (siRNA) independently of all endocytotic pathways. Indeed, siRNA therapeutic interest lies on its ability to inhibit specifically deregulated proteins in the context of pathology. The subject of my thesis focused on the characterization and optimization of CADY/siRNA complexes. During my work, we have been able to show that CADY adopts a helical structure while interacting with the siRNA leading to the formation of nanoparticles. The goal of my study was to optimize CADY sequence and control its formulation to consider the transferring from an in cellulo to an in vivo application of our vectorization system. First, we conducted a structure-activity study with six analogues by mutating CADY on tryptophane residues (PSF1, 2, 3 and PSW) and in the area initializing helical structure (PG9, PG16). A thorough analysis of these analogues has confirmed that the limitation of the amphipathic character and structural polymorphism is directly related to the reduction of internalization efficiency of our CPPs. Among the six analogues, only PG16/siRNA and PG9/siRNA nanoparticles show in cellulo results equal to those obtained with CADY/siRNA. Based on the fact, that CADY is the most suitable vector for the transfection of therapeutic molecules such as siRNA, we have established a standard formulation procedure to obtain reproducible and homogeneous CADY/siRNA complexes with an average size of 106 ± 31 nm and a polydispersity index of 0.357 ± 0.053. In addition, we have implemented an extrusion/lyophilization step to allow nanoparticle storage as powder, which can be re-suspended in an aqueous solution without losing their colloidal and transfection properties.In order to improve tissue specificity and bioavailability of CADY/siRNA nanoparticles for an in vivo application, we have grafted ether a targeting sequence (YIGSR-S) or a stealth motif (PEG) to the CADY sequence. These two entities of very different nature provoke only few changes in the physicochemical (e.g. average size) and biological (cell transfection) characteristics of the nanoparticles formed with a siRNA. These results are very encouraging for the development of the so-called 3rd nanoparticle generation which includes several kinds of molecules (targeting, polymer, contrast agent etc.).These outcomes mark the real progress in CADY formulation optimization, and encourage us to further exploit its potential for the in vivo transfer of siRNA.

Chez les eucaryotes supérieurs, la progression ordonnée du cycle cellulaire est régie par une dizaine de kinases Cdk-cyclines. Les altérations génétiques ou épigénétiques impliquant des oncogènes ou des gènes codant pour des suppresseurs de tumeurs sont souvent associées à l'expression ou l'activation aberrante des Cdks, favorisant ainsi la prolifération cellulaire incontrôlée et notamment le développement de cancers. Malgré la pertinence oncogénique et thérapeutique de ces protéines, leur détection est restée jusqu'à présent limitée à des méthodes indirectes et invasives. Dans ce contexte, mes travaux de thèse ont permis de développer un biosenseur peptidique fluorescent permettant de reconnaître spécifiquement les Cdk-cyclines. Associé à une stratégie de vectorisation non invasive basée sur l'utilisation de peptides vecteurs pénétrants, le biosenseur a été délivré efficacement dans les cellules. La mise au point d'une quantification ratiométrique du signal a par ailleurs permis d'évaluer l'abondance relative des Cdk-cyclines endogènes. Deux variants plus spécifiques de certains complexes ont pu être développés. Enfin, d'autres versions du biosenseur ont quant à elles permis d'évaluer sa biodistribution in vivo et de mettre au point un essai cellulaire en vue d'un criblage de petites molécules ayant un effet sur l'abondance relative des Cdk-cyclines. / Cdk-cyclins represent key regulators of cell cycle progression among superior eukaryotes. Genetic and epigenetic alterations involving oncogenes or tumor suppressor genes are often associated with aberrant expression or activation of Cdks, leading to the sustained proliferation of cells and by the way to the development of cancers. Despite the oncogenic and therapeutic relevance of these proteins, their detection has so far remained limited to indirect and invasive methods. My Ph.D. thesis work aimed in this context at developing peptidic fluorescent biosensors that specifically recognize Cdk-cyclins. Combined to cell-penetrating peptides, the biosensor was efficiently delivered into cells. Following the development of the signal ratiometric quantification, the relative abundance of endogenous Cdk-cyclins was directly evaluated in living cells. Two other variants, that are more specific towards specific Cdk-cyclin complexes, were also designed. Finally, the development of novel versions of the biosensor allowed us to evaluate its biodistribution in vivo and to set up a cell-based assay to screen small molecules having an effect on Cdk-cyclin relative abundance.

The subject of this master’s thesis is the diagnostic survey of the industry cast-in-place hall. The thesis contains theoretical and practical part. The theoretical part is focused on available options of diagnostic methods and options of materials evaluation. The practical part contains material assessment of chosen elements of construction. This part of thesis is focused on localizing the position and the diameter of reinforcement in every single element. Next step is focused on the quality of the concrete, particularly compressive strength and modulus of elasticity. The modern machines, like Hilti PS 1000 and Profometer PM-630, are used to localize the position and diameter of reinforcement. The quality of concrete is determined by removed bore core. Evaluation of material characteristics of the structure is in the conclusion.

Le contrôle des chaussées neuves en génie civil est primordial pour assurer sa bonne miseen oeuvre et lui conférer une durée de vie optimale. Dans cet objectif, divers paramètresphysiques nécessitent d'être scrupuleusement calibrés et contrôlés afin d'éviter une dégradation précoce de la chaussée et des problèmes de sécurité pour les conducteurs qui l'empruntent. De plus, les coûts associés à la mise en place et à la maintenance des chaussées sont considérables. Parmi les propriétés qui requièrent une attention particulière, la compacité, qui est indicative de la quantité d'air en volume dans la chaussée, est celle qui nous intéresse dans cette étude. Actuellement, seulement deux méthodes en laboratoire (en Europe) sont considérées comme des méthodes normalisées pour déterminer la compacité. Néanmoins, ces techniques sont destructives et/ou nucléaires ce qui est un frein majeur à leur utilisation. Durant ces deux dernières décennies, de nouvelles techniques électromagnétiques (non nucléaires et non destructives) ont émergé et ont prouvé leur forte utilité dans le domaine de la géophysique et du génie civil et plus particulièrement pour la détermination de la compacité. Cependant, ces nouvelles techniques nécessitent de prendre un certain nombre de précautions pour déterminer la compacité. Tout d'abord, elles permettent de mesurer la permittivité diélectrique du matériau en question. Ainsi pour déterminer la compacité, il est nécessaire d'utiliser des lois de mélange électromagnétiques. L'utilisation de ces modèles requiert une connaissance précise des constituants qui composent la chaussée ainsi que de leurs propriétés (masse volumique et permittivité diélectrique). La première partie de ce travail démontre la pertinence d'utiliser un radar à sauts de fréquences pour déterminer la compacité. L'étude de plusieurs lois de mélange électromagnétiques a été réalisée et les modèles présentant les meilleurs résultats ont été sélectionnés. Cependant, ces techniques font face de nos jours à un problème majeur. En effet, l'utilisation de matériaux recyclés est de plus en plus fréquente pour la construction de nouvelles chaussées ce qui rend la détermination de la compacité encore plus difficile par des méthodes électromagnétiques. Par conséquent, plusieurs méthodologies ont été développées, et sont proposées pour déterminer la compacité d'une nouvelle autoroute qui comporte des matériaux recyclés. La seconde partie de ces travaux de recherche porte sur la caractérisation diélectrique de plusieurs roches qui sont les éléments principaux d'une chaussée. Cette caractérisation est validée de basses à hautes fréquences mais aussi en fonction de la température. Les résultats montrent que à haute fréquence, la permittivité est principalement dépendante de la densité et de la composition chimique de la roche. En revanche, lorsque la fréquence d'investigation diminue et que la température varie, d'autres phénomènes apparaissent et changent dramatiquement le comportement diélectrique de la roche. Il a également été montré que l'eau joue un rôle majeur dans le comportement diélectrique à basse fréquence de la roche. Ces phénomènes se répercutent à "haute fréquence" par de très faibles variations qui pourraient expliquer les déviations obtenues par les méthodes électromagnétiques capacitives qui fonctionnent dans la région du MHz et qui sont également utilisées pour le contrôle de la compacité des chaussées neuves. / The control of new paved road is primordial to ensure its quality as well as its lifetime. Thus, several physical properties need to be well calibrated and controlled in order to avoid early degradations and safety issues for the drivers. Furthermore, the coast associated to the road building and the road maintenance is significant which makes the implementation of asphalt pavement according to the standard even more important. Among the properties that need attentions, the compactness which is indicative of the air void concentration in the asphalt pavement is the one we are interested in. Currently, only two methods in laboratory (in Europe) are considered as standards to assess the compactness. Nevertheless, these techniques are either nuclear or destructive which is a major hindrance. In the past two decades, new electromagnetic (EM) techniques have emerged and proved their great utility for geophysics or civil engineering applications and more importantly for the compactness assessment. However, these non-destructive and non-nuclear methods require many special precautions for the compactness assessment. First of all, they allow to measure the dielectric permittivity of the investigated material. Then to figure out the compactness, the use of EM mixing models is required. This leads to the accurate knowledge of every components constituting the asphalt pavement and their related properties (density and permittivity). The first main part of this work spotlights the relevance of using a step frequency radar for the compactness assessment. The study of several EM mixing models is performed to select the most appropriate ones. Nowadays, one of the challenges to address for these techniques is that the use of recycled materials is more and more commonly implemented for new roads building. Indeed, as the knowledge of the component properties is required, this makes the compactness assessment even more difficult. As a consequence, several methods have been developed and are proposed to assess the compactness of a new paved highway containing recycled asphalt pavement. The second main part of this research is the dielectric characterization of many rocks which are the main component of the asphalt pavement. This characterization is validated from low to high frequencies and also as a function of the temperature. The results show at high frequency that the permittivity is mainly dependent on the density and the chemical composition of the rock. However, as the frequency decreases and the temperature varies, this is not longer true and additional phenomena appear and drastically change the dielectric behavior of the rock. Also, it has been shown that the water plays a major role on the dielectric behavior at low frequency. This phenomena are reflected partially by small variations at "high frequency" that could explained the deviations obtained for capacitive techniques which work in the MHz region and which are used also for the compactness assessment.

Understanding modern carbonate depositional systems gives valuable insights into the interpretation of ancient carbonate systems. Ancient carbonate strand plains have the potential to act as productive hydrocarbon reservoirs because of their relatively high porosity. Unfortunately, they are difficult to identify in the rock record because of the lack of work done on modern analogues. San Salvador Island in the Bahamas hosts a well-exposed and easily accessible Holocene strand plain, ideal as a modern analogue. Sandy Hook, located on the southeast part of the island, consists of approximately 35 ridge-swale features that show signs of four distinct zones of deposition. In this study, 20 sediment samples were collected from one meter in depth, and throughout each zone. The sediment analysis reveals remarkably consistent grain-size distributions across the four zones. Carbon-14 ages were taken from the sediment samples. They revealed ages decreasing from 2617 ± 188 YBP to modern moving seaward through zone 4. The ages reveal depositional rates of 0.08 to 0.29 meters of accretion per year. Four pseudo-3D GPR surveys were acquired in Zones B, C, and D, and a 2D GPR survey was acquired that spanned the three zones. The pseudo-3D surveys revealed consistent reflectors through the width of the survey indicating that the 2D surveys represent more than the single line. The 2D survey reveals semi-parallel seaward-dipping reflectors (representing fair-weather deposits) that are truncated by sigmoidal seaward-dipping reflectors (high-energy storm deposits). Indicating that Sandy Hook was built through both fair-weather deposits and high-energy storm events.

High cost is a current problem with modern radar systems. Software-defined radios (SDRs) offer a possible solution for low-cost customizable radar systems. An SDR is a radio communi- cation system where, instead of the traditional radio components implemented in hardware, many of the components are implemented in software on a computer or embedded system. Although SDRs were originally designed for wireless communication systems, the firmware of an SDR can be configured into a radar system. With new companies entering the market, various types of low- cost SDRs have emerged. This thesis explores the use of a LimeSDR-Mini in a short-range radar through open software tools and custom code. The LimeSDR-Mini is successfully shown to detect targets at a short range. However, due to the instability of the LimeSDR-Mini, the consistent detection of a target is not possible. This thesis shows how the LimeSDR is characterized and how timing synchronization and instability issues are mitigated. The LimeSDR-Mini falls short of operating reliable in a radar system and other SDR boards need to be explored as viable options. Test setups using coaxial cables and test setups using antennas in an outdoor environment show the instability of the LimeSDR-Mini. The transmitter and the receiver are asynchronous. The timing difference varies slightly from run to run, which results in issues that are exacerbated in a short-range radar. The bleed-through signal is the signal leakage from the transmitter to the receiver. The bleed-through signal prevents the detection of targets at a short-range. Feed-through nulling is a signal processing technique used to eliminate the bleed-through signal so that short- range targets can be detected. The instability of the LimeSDR-Mini reduces the effectiveness of feed-through nulling techniques.

<p>Pathogenic bacteria present a critical threat to modern medicine. Therapeutic strategies to target and eliminate resilient bacteria are not advancing at the same rate as the emergence of bacterial resistance. An associated urgent concern regarding antibiotic resistance is the existence and proliferation of intracellular bacteria, which find refuge from bactericidal mechanisms by hiding within mammalian cells. Therefore, many once-successful antibiotics become ineffective through the development of resistance, or through failure to reach intracellular locations in therapeutic concentration. To overcome these challenges, the covalent combination of a conventional antibiotic with an antibiotic, cell-penetrating peptide was explored to develop dual-action antibiotic conjugates. </p> <p>Herein, we utilized a strategy in conjugating the antibiotics by a cleavable linkage to cationic amphiphilic polyproline helices (CAPHs) to improve vancomycin and linezolid antibiotics. This approach enables the conjugate to penetrate cells and deliver two potent monomeric antimicrobial drugs. The vancomycin-CAPH conjugate, <b>VanP14S</b>, showed enhanced mammalian cell uptake compared to vancomycin, a poor mammalian cell-penetrating agent; and <b>VanP14S</b> was capable of cleaving and releasing two antibiotics under mimicked physiological conditions. Enhanced antibacterial activity was observed against a spectrum of Gram-positive and Gram-negative pathogens, including drug-resistant strains. Further investigation revealed that this conjugate’s bactericidal activity was not entirely the result of significant membrane perturbation such as a lytic mode of action. Mammalian cell toxicity and red blood cell lysis were insignificant at relevant bactericidal concentrations below 20 µM. The current results suggest an enhanced binding to the peptidoglycan of bacteria, the target of vancomycin, although more work is needed to justify this claim. Preliminary results on <b>VanP14GAPS</b>, a conjugate with a more rigid CAPH, convey similar activity to <b>VanP14S; </b>however,<b> </b>moderate increases in red blood cell lysis and cytotoxicity were observed. </p> <p>Regarding the <b>LnzP14</b> conjugate, preliminary data reveal that the conjugate has Gram-negative activity against <i>Escherichia coli</i>, whereas linezolid is ineffective in killing Gram-negative bacteria. This conjugate showed significant enhancement in cellular uptake compared to the CAPH, and the release of linezolid and CAPH in physiological conditions was confirmed. Overall, arming a conventional antibiotic with an antimicrobial, cell-penetrating peptide appears to be a powerful strategy in providing novel antibiotic conjugates with the propensity to overcome the limitations in treating challenging pathogens.</p>