A Multifunctional Subphthalocyanine Nanosphere for Targeting,Labeling, and Killing of Antibiotic‐Resistant Bacteria

Developing a material that can combat antibiotic‐resistant bacteria, a major global health threat, is an urgent requirement. To tackle this challenge, we synthesized a multifunctional subphthalocyanine (SubPc) polymer nanosphere that has the ability to target, label, and photoinactivate antibiotic‐resistant bacteria in a single treatment with more than 99 % efficiency, even with a dose as low as 4.2 J cm⁻² and a loading concentration of 10 nM . The positively charged nanosphere shell composed of covalently linked SubPc units can increase the local concentration of photosensitizers at therapeutic sites. The nanosphere shows superior performance compared to corresponding monomers presumably because of their enhanced water dispersibility, higher efficiency of singlet‐oxygen generation, and phototoxicity. In addition, this material is useful in fluorescence labeling of living cells and shows promise in photoacoustic imaging of bacteria in vivo.     

Boronic Acid Functionalized Photosensitizers: A Strategy To Target the Surface of Bacteria and Implement Active Agents in Polymer Coatings

Advanced methods for preventing and controlling hospital‐acquired infections via eradication of free‐floating bacteria and bacterial biofilms are of great interest. In this regard, the attractiveness of unconventional treatment modalities such as antimicrobial photodynamic therapy (aPDT) continues to grow. This study investigated a new and innovative strategy for targeting polysaccharides found on the bacterial cell envelope and the biofilm matrix using the boronic acid functionalized and highly effective photosensitizer (PS) silicon(IV) phthalocyanine. This strategy has been found to be successful in treating planktonic cultures and biofilms of Gram‐negative E. coli. An additional advantage of boronic acid functionality is a possibility to anchor the tailor made PS to poly(vinyl alcohol) and to fabricate a self‐disinfecting coating.     

A Glycosylated Cationic Block Poly(β-peptide) Reverses Intrinsic Antibiotic Resistance in All ESKAPE Gram-Negative Bacteria

Carbapenem-resistant Gram-negative bacteria (GNB) are heading the list of pathogens for which antibiotics are the most critically needed. Many antibiotics are either unable to penetrate the outer-membrane or are excluded by efflux mechanisms. Here, we report a cationic block β-peptide (PAS8-b-PDM12) that reverses intrinsic antibiotic resistance in GNB by two distinct mechanisms of action. PAS8-b-PDM12 does not only compromise the integrity of the bacterial outer-membrane, it also deactivates efflux pump systems by dissipating the transmembrane electrochemical potential. As a result, PAS8-b-PDM12 sensitizes carbapenem- and colistin-resistant GNB to multiple antibiotics in vitro and in vivo. The β-peptide allows the perfect alternation of cationic versus hydrophobic side chains, representing a significant improvement over previous antimicrobial α-peptides sensitizing agents. Together, our results indicate that it is technically possible for a single adjuvant to reverse innate antibiotic resistance in all pathogenic GNB of the ESKAPE group, including those resistant to last resort antibiotics.     

Utilizing Paper‐Based Devices for Antimicrobial‐Resistant Bacteria Detection

Antimicrobial resistance (AMR), the ability of a bacterial species to resist the action of an antimicrobial drug, has been on the rise due to the widespread use of antimicrobial agents. Per the World Health Organization, AMR has an estimated annual cost of USD 34 billion in the US and is predicted to be the number one cause of death worldwide by 2050. One way AMR bacteria can spread, and by which individuals can contract AMR infections, is through contaminated water. Monitoring AMR bacteria in the environment currently requires that samples be transported to a central laboratory for slow and labor intensive tests. We have developed an inexpensive assay using paper‐based analytical devices (PADs) that can test for the presence of β‐lactamase‐mediated resistance. To demonstrate viability, the PAD was used to detect β‐lactam resistance in wastewater and sewage and identified resistance in individual bacterial species isolated from environmental water sources.     

19F‐NMR Reveals the Role of Mobile Loops in Product and Inhibitor Binding by the São Paulo Metallo‐β‐Lactamase

Resistance to β‐lactam antibiotics mediated by metallo‐β‐lactamases (MBLs) is a growing problem. We describe the use of protein‐observe ¹⁹F‐NMR (PrOF NMR) to study the dynamics of the São Paulo MBL (SPM‐1) from β‐lactam‐resistant Pseudomonas aeruginosa . Cysteinyl variants on the α3 and L3 regions, which flank the di‐Zn^II active site, were selectively ¹⁹F‐labeled using 3‐bromo‐1,1,1‐trifluoroacetone. The PrOF NMR results reveal roles for the mobile α3 and L3 regions in the binding of both inhibitors and hydrolyzed β‐lactam products to SPM‐1. These results have implications for the mechanisms and inhibition of MBLs by β‐lactams and non‐β‐lactams and illustrate the utility of PrOF NMR for efficiently analyzing metal chelation, identifying new binding modes, and studying protein binding from a mixture of equilibrating isomers.     

From Genome to Proteome to Elucidation of Reactions for All Eleven Known Lytic Transglycosylases from Pseudomonas aeruginosa

An enzyme superfamily, the lytic transglycosylases (LTs), occupies the space between the two membranes of Gram‐negative bacteria. LTs catalyze the non‐hydrolytic cleavage of the bacterial peptidoglycan cell‐wall polymer. This reaction is central to the growth of the cell wall, for excavating the cell wall for protein insertion, and for monitoring the cell wall so as to initiate resistance responses to cell‐wall‐acting antibiotics. The nefarious Gram‐negative pathogen Pseudomonas aeruginosa encodes eleven LTs. With few exceptions, their substrates and functions are unknown. Each P. aeruginosa LT was expressed as a soluble protein and evaluated with a panel of substrates (both simple and complex mimetics of their natural substrates). Thirty‐one distinct products distinguish these LTs with respect to substrate recognition, catalytic activity, and relative exolytic or endolytic ability. These properties are foundational to an understanding of the LTs as catalysts and as antibiotic targets.     

Detection of Carbapenemase‐Producing Organisms with a Carbapenem‐Based Fluorogenic Probe

Antibiotic resistance has become a major challenge to public health worldwide. This crisis is further aggravated by the increasing emergence of bacterial resistance to carbapenems, typically considered as the antibiotics of last resort, which is mainly due to the production of carbapenem‐hydrolyzing carbapenemases in bacteria. Herein, the carbapenem‐based fluorogenic probe CB‐1 with an unprecedented enamine–BODIPY switch is developed for the detection of carbapenemase activity. This reagent is remarkably specific towards carbapenemases over other prevalent β‐lactamases. Furthermore, the efficient imaging of live clinically important carbapenemase‐producing organisms (CPOs) with CB‐1 demonstrates its potential for the rapid detection of antibiotic resistance and timely diagnosis of CPO infections.