This report describes the preparation of polyacrylate nanoparticles in which an N-thiolated β-lactam antibiotic is covalently conjugated onto the polymer framework. These nanoparticles are formed in water by emulsion polymerization of an acrylated antibiotic pre-dissolved in a liquid acrylate monomer (or mixture of co-monomers) in the presence of sodium dodecyl sulfate as a surfactant and potassium persulfate as a radical initiator. Dynamic light scattering analysis and electron microscopy images of these emulsions show that the nanoparticles are approximately 40 nm in diameter. The emulsions have potent in vitro antibacterial properties against methicillin-resistant Staphylococcus aureus and have improved bioactivity relative to the non-polymerized form of the antibiotic. A unique feature of this methodology is the ability to incorporate water-insoluble drugs directly into the nanoparticle framework without the need for post-synthetic modification. Additionally, the antibiotic properties of the nanoparticles can be modulated by changing the length or location of the acrylate linker on the drug monomer.The development of antibiotics for control of pathogenic bacteria has been of pressing need in this era of drug-resistant infections. 1 N-Methylthiolated β-lactams have recently been identified in our laboratory as a new family of antibacterial agents active against Staphylococcus bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). 2 The compounds have also displayed promising anticancer properties. 3 Our recent studies have suggested that these lactams exert their growth inhibitory effects on bacteria through a mode of action that is distinctively different to that of other β-lactam antibiotics, and possess structure-activity patterns unlike those already mapped for other β-lactam antibacterials such as the penicillins. One of the major limitations in the potential application of these N-thiolated β-lactam compounds, however, is their exceedingly low water solubility. 4 Thus, we were interested in identifying an effective drug delivery platform that would enhance the water solubility of the lactams, without sacrificing inherent bioactivity.Drug delivery vehicles such as liposomes and gold nanoparticles have been developed to improve bioavailability, efficacy, and specificity of pharmaceutical compounds, particularly for anticancer agents, but nanoparticles have received surprisingly little attention in the Supporting Information Available: Synthetic procedures, physical characterization, antibacterial and cytotoxicity data for lactams 1-4 and nanoparticles NP0-4.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the conten...

This report describes the preparation of antibacterially-active emulsified polyacrylate nanoparticles in which a penicillin antibiotic is covalently conjugated onto the polymeric framework. These nanoparticles were prepared in water by emulsion polymerization of an acrylated penicillin analogue pre-dissolved in a 7:3 (w:w) mixture of butyl acrylate and styrene in the presence of sodium dodecyl sulfate (surfactant) and potassium persulfate (radical initiator). Dynamic light scattering analysis and atomic force microscopy images show that the emulsions contain nanoparticles of approximately 40 nm in diameter. The nanoparticles have equipotent in vitro antibacterial properties against methicillin-susceptible and methicillin-resistant forms of Staphylococcus aureus and indefinite stability towards β-lactamase.The continuing rise in microbial drug resistance has led to widespread problems in the treatment of bacterial infections. 1 Of particular concern are those illnesses caused by methicillin-resistant Staphylococcus aureus (MRSA), which are responsible for a majority of hospital-acquired infections, clinical complications, and nearly 100,000 deaths each year in the United States alone. 2,3 The loss of effectiveness of commonly used antibacterial antibiotics such as penicillin and other β-lactam drugs further adds to the dilemma, calling for the immediate need for improvements in drug design, discovery, and delivery. One of the major challenges in treating antibiotic-resistant bacterial infections is the need to develop agents that can stop the infection at the site of initiation, which frequently occurs in regions of the body where water-soluble drugs typically have poor access. However, the application of lipophilic agents to combat such infections likewise has limited effectiveness due to uptake and delivery issues resulting from low water solubility and biodistribution. 4 The ability to deliver antibacterial drugs to infections in fatty tissue or on the surface of implanted medical devices, for example, where microbial biofilms often develop, ultimately determines if the infection can be cleared without surgical intervention. 5 New drug delivery vehicles such as liposomes and nanoparticles offer a promising way to improve bioavailability, efficacy, and specificity of pharmaceutical compounds in general. Several groups have reported previously on the preparation and antibacterial testing of various penicillin-or ampicillin-entrapped polycyanoacrylates formed by anionic emulsion polymerization in water. 6-15 These emulsified suspensions consisted of drug-containing particles considerably larger than 100 nm in diameter, and reportedly provided Correspondence to: Edward Turos. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Plea...

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Studies on Nonconventionally Fused Bicyclic β-Lactams.-A number of structurally novel [3.2.0]bicyclic β-lactam ring systems such as (IV), (IX), and (XIV) that have the lactam functionality arranged in alternative orientations within the four-membered ring are prepared. Semiempirical calculations indicate that the thermodynamic stabilities of the alternative isomeric ring systems are similar to that of the classical structure. The derivatives (Xb) and (XVI) show weak activity against Staphylococcus aureus or Vibrio cholerae.