Correction to "Antibiotic Adjuvants: A Versatile Approach to Combat Antibiotic Resistance".

[This corrects the article DOI: 10.1021/acsomega.3c00312.][This corrects the article DOI: 10.1021/acsomega.3c03063.].

Antimicrobial nanocomposite coatings for rapid intervention against catheter-associated urinary tract infections.

Catheter-associated urinary tract infections (CAUTIs) pose a significant challenge in hospital settings. Current solutions available on the market involve incorporating antimicrobials and antiseptics into catheters. However, challenges such as uncontrolled release leading to undesirable toxicity, as well as the prevalence of antimicrobial resistance reduce the effectiveness of these solutions. Additionally, conventional antibiotics fail to effectively eradicate entrenched bacteria and metabolically suppressed bacteria present in the biofilm, necessitating the exploration of alternative strategies. Here, we introduce a novel polymer-nanocomposite coating that imparts rapid antimicrobial and anti-biofilm properties to coated urinary catheters. We have coated silicone-based urinary catheters with an organo-soluble antimicrobial polymer nanocomposite (APN), containing hydrophobic quaternized polyethyleneimine and zinc oxide nanoparticles, in a single step coating process. The coated surfaces exhibited rapid eradication of drug-resistant bacteria within 10-15 min, including E. coli, K. pneumoniae, MRSA, and S. epidermidis, as well as drug-resistant C. albicans fungi. APN coated catheters exhibited potent bactericidal activity against uropathogenic strains of E. coli, even when incubated in human urine. Furthermore, the stability of the coating and retention of antimicrobial activity was validated even after multiple washes. More importantly, this coating deterred biofilm formation on the catheter surface, and displayed rapid inactivation of metabolically repressed stationary phase and persister cells. The ability of the coated surfaces to disrupt bacterial membranes and induce the generation of intracellular reactive oxygen species (ROS) was assessed through different techniques, such as electron microscopy imaging, flow cytometry as well as fluorescence spectroscopy and microscopy. The surface coatings were found to be biocompatible in an in vivo mice model. Our simple one-step coating approach for catheters holds significant potential owing to its ability to tackle multidrug resistant bacteria and fungi, and the challenge of biofilm formation. This work brings us one step closer to enhancing patient care and safety in hospitals.

Cleavable Amphiphilic Biocides with Ester-Bearing Moieties: Aggregation Properties and Antibacterial Activity.

The rise of multidrug-resistant bacterial infections and the dwindling supply of newly approved antibiotics have emerged as a grave threat to public health. Toward the ever-growing necessity of the development of novel antimicrobial agents, herein, we synthesized a series of cationic amphiphilic biocides featuring two cationic headgroups separated by different hydrophobic spacers, accompanied by the inclusion of two lipophilic tails through cleavable ester functionality. The detailed aggregation properties offered by these biocides were investigated by small-angle neutron scattering (SANS) and conductivity. The critical micellar concentration of the biocides and the size and shape of the micellar aggregates differed with variation of pendant and spacer hydrophobicity. Furthermore, the aggregation number and size of the micelles were found to vary with changing concentration and temperature. These easily synthesized biocides exhibited potent antibacterial properties against various multidrug-resistant bacteria. The optimized biocides with minimum hematotoxicity and potent antibacterial activity against methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii exhibited rapid killing kinetics against planktonic bacteria. Also, these membrane-active agents were able to eradicate preformed biofilms. The enzymatic and acidic degradation profile further offered proof of gradual degradation. Collectively, these cleavable amphiphilic biocides demonstrated excellent potency for combating the multidrug-resistant bacterial infection.

Dual functional therapeutics: mitigating bacterial infection and associated inflammation.

The emergence of antimicrobial resistance, coupled with the occurrence of persistent systemic infections, has already complicated clinical therapy efforts. Moreover, infections are also accompanied by strong inflammatory responses, generated by the host's innate and adaptive immune systems. The closely intertwined relationship between bacterial infection and inflammation has multiple implications on the ability of antibacterial therapeutics to tackle infection and inflammation. Particularly, uncontrolled inflammatory responses to infection can lead to sepsis, a life-threatening physiological condition. In this review, we discuss dual-functional antibacterial therapeutics that have potential to be developed for treating inflammation associated with bacterial infections. Immense research is underway that aims to develop new therapeutic agents that, when administered, regulate the excess inflammatory response, i.e. they have immunomodulatory properties along with the desired antibacterial activity. The classes of antibiotics that have immunomodulatory function in addition to antibacterial activity have been reviewed. Host defense peptides and their synthetic mimics are amongst the most sought-after solutions to develop such dual-functional therapeutics. This review also highlights the important classes of peptidomimetics that exhibit both antibacterial and immunomodulatory properties.

Erratum: Antibiotic Adjuvants: A Versatile Approach to Combat Antibiotic Resistance.

[This corrects the article DOI: 10.1021/acsomega.3c00312.].

Antibiotic Adjuvants: A Versatile Approach to Combat Antibiotic Resistance.

The problem of antibiotic resistance is on the rise, with multidrug-resistant strains emerging even to the last resort antibiotics. The drug discovery process is often stalled by stringent cut-offs required for effective drug design. In such a scenario, it is prudent to delve into the varying mechanisms of resistance to existing antibiotics and target them to improve antibiotic efficacy. Nonantibiotic compounds called antibiotic adjuvants which target bacterial resistance can be used in combination with obsolete drugs for an improved therapeutic regime. The field of "antibiotic adjuvants" has gained significant traction in recent years where mechanisms other than ß-lactamase inhibition have been explored. This review discusses the multitude of acquired and inherent resistance mechanisms employed by bacteria to resist antibiotic action. The major focus of this review is how to target these resistance mechanisms by the use of antibiotic adjuvants. Different types of direct acting and indirect resistance breakers are discussed including enzyme inhibitors, efflux pump inhibitors, inhibitors of teichoic acid synthesis, and other cellular processes. The multifaceted class of membrane-targeting compounds with poly pharmacological effects and the potential of host immune-modulating compounds have also been reviewed. We conclude with providing insights about the existing challenges preventing clinical translation of different classes of adjuvants, especially membrane-perturbing compounds, and a framework about the possible directions which can be pursued to fill this gap. Antibiotic-adjuvant combinatorial therapy indeed has immense potential to be used as an upcoming orthogonal strategy to conventional antibiotic discovery.

Pursuit of next-generation glycopeptides: a journey with vancomycin.

Vancomycin, a blockbuster antibiotic of the glycopeptide class, has been a life-saving therapeutic against multidrug-resistant Gram-positive infections. The emergence of glycopeptide resistance has however enunciated the need to develop credible alternatives with potent activity against vancomycin-resistant bacteria. Medicinal chemistry has responded to this challenge through various strategies, one of them being the development of semisynthetic analogues. Many groups, including ours, have been contributing towards the development of semisynthetic vancomycin analogues to tackle vancomycin-resistant bacteria. In this feature article, we have discussed our research contribution to the field of glycopeptides, which includes our strategies and designs of vancomycin analogues incorporating multimodal mechanisms of action. The strategies discussed here, such as conferring membrane activity, enhanced binding to target, multivalency, etc. involve semisynthetic modifications to vancomycin at the carboxy terminal and the amino group of the vancosamine sugar of vancomycin, to develop novel analogues. These analogues have demonstrated their superior efficacy in tackling the inherited forms of vancomycin resistance in Gram-positive and Gram-negative bacteria, including highly drug-resistant strains. More importantly, these analogues also possess the ability to tackle various non-inherited forms of bacterial resistance, such as metabolically dormant stationary-phase and persister cells, bacterial biofilms, and intracellular pathogens. Our derivatives also display superior pharmacokinetics, and less propensity for resistance development, owing to their different modes of action. Through this feature article, we present to the reader a concise picture of the multitude of approaches that can be used to tackle different types of resistance through semisynthetic modifications to vancomycin. We have also highlighted the challenges and lacunae in the field, and potential directions which future research can explore.

Emerging Roles of Glycopeptide Antibiotics: Moving beyond Gram-Positive Bacteria.

Glycopeptides, a class of cell wall biosynthesis inhibitors, have been the antibiotics of choice against drug-resistant Gram-positive bacterial infections. Their unique mechanism of action involving binding to the substrate of cell wall biosynthesis and substantial longevity in clinics makes this class of antibiotics an attractive choice for drug repurposing and reprofiling. However, resistance to glycopeptides has been observed due to alterations in the substrate, cell wall thickening, or both. The emergence of glycopeptide resistance has resulted in the development of synthetic and semisynthetic glycopeptide analogues to target acquired resistance. Recent findings demonstrate that these derivatives, along with some of the FDA approved glycopeptides have been shown to have antimicrobial activity against Gram-negative bacteria, Mycobacteria, and viruses thus expanding their spectrum of activity across the microbial kingdom. Additional mechanisms of action and identification of novel targets have proven to be critical in broadening the spectrum of activity of glycopeptides. This review focuses on the applications of glycopeptides beyond their traditional target group of Gram-positive bacteria. This will aid in making the scientific community aware about the nontraditional activity profiles of glycopeptides, identify the existing loopholes, and further explore this antibiotic class as a potential broad-spectrum antimicrobial agent.