An optimum hydrophilic/hydrophobic balance has been recognized as a crucial parameter in designing cationic polymers that mimic antimicrobial peptides (AMPs). To date, this balance was achieved either by hydrophilicity variation through altering the nature and the number of cationic charges or by hydrophobicity modulation through incorporation of alkyl groups of different chain lengths. However, how the hydrophobicity variation through AMPs' building blocksamino acidsinfluences the antibacterial efficacy of AMP-mimicking cationic polymers has rarely been explored. Toward this goal, herein we report a class of amino acid conjugated polymers (ACPs) with tunable antibacterial activity through a simple post-polymer-functionalization strategy. Our polymeric design comprised a permanent cationic charge in every repeating unit, whereby the hydrophobicity was tuned through incorporation of different amino acids. Our results revealed that the amino acid alteration has a strong influence on antibacterial efficacy. Upon increasing the amino acid side-chain hydrophobicity, both the antibacterial activity (against broad spectrum of bacteria) and toxicity increased. However, the distinct feature of this class of polymers was their good activity against Acinetobacter baumanniithe top most critical pathogen according to WHO, which has created an alarming situation worldwide, causing the majority of infections in humans. A nontoxic (no hemolysis even at 1000 μg/mL) ACP including a glycine residue (ACP-1 (Gly)) showed very good activity (MIC = 8−16 μg/mL) against both drug-sensitive and drug-resistant strains of A. baumannii, including clinical isolates. This polymer not only was rapidly bactericidal against growing planktonic A. baumannii but also killed nondividing stationary-phase cells instantaneously (<2 min). Moreover, it eradicated the established biofilm formed by drug-resistant A. baumannii clinical isolates. No propensity for bacterial resistance development against this polymer was seen even after 14 continuous passages. Taken together, the results highlight that hydrophobicity modulation through incorporation of amino acids in cationic polymers will provide a significant opportunity in designing new ACPs with potent antibacterial activity and minimum toxicity toward mammalian cells. More importantly, the excellent anti-A. baumannii efficacy of the optimized lead polymer indicates its immense potential for being developed as therapeutic agent.

The ever increasing threats of Gram-positive superbugs such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and vancomycin-resistant Enterococccus faecium (VRE) are serious matter of concern worldwide toward public health. Such pathogens cause repeated recurrence of infections through the formation of biofilms which consist of metabolically inactive or slow growing dormant bacterial population in vast majority. Concurrently, dispersal of biofilms originates even more virulent dispersed cells responsible for pathogenesis. Along with this, fungal infections most commonly associated with Candida albicans also created a major complicacy in human healthcare. Moreover, concomitant survival of C. albicans and MRSA in a multispecies biofilms created extremely complicated polymicrobial infections. Surprisingly, infections associated with single species biofilm as well as multiple species biofilm (co-existence of MRSA and C. albicans) are almost untreatable with conventional antibiotics. Therefore, the situation demands an urgent development of antimicrobial agent which would tackle persistent infections associated with bacteria, fungi and their biofilms. Toward this goal, herein we developed a new class of branched polyethyleneimine based amphiphilic cationic macromolecules (ACMs) bearing normal alkyl, alkyl ester and alkyl amide moieties. An optimized compound with dual activity against drug-resistant bacteria (MIC = 2-4 µg/mL) and fungi (MIC = 4-8 µg/mL) was identified with minimal toxicity toward human erythrocytes (HC 50 = 270 µg/mL). The lead compound, ACM-A Hex (12) displayed rapid bactericidal and fungicidal kinetics (>5 log CFU/mL reduction within 1-4 h). It also killed metabolically dormant stationary (MRSA and VRE) and persister (S. aureus) cells. Moreover, this compound was able to disrupt the preformed biofilm of MRSA and reduced the bacterial burden related to the dispersed cells. It showed significant proficiencies to eliminate polymicrobial biofilms of MRSA and C. albicans. Bacteria also could not develop any resistant against this class of membrane active molecules even after 15 days of successive passages. Taken together this class of macromolecule can be developed further as a dual therapeutic agent to combat infections associated with bacterial and fungal coexistence .

Rapid emergence of multidrug-resistant Gram-negative pathogens coupled with their biofilm-forming capability have set a clinical ultimatum to global public health with an increasing rate of mortality. Recently, the World Health Organization (WHO) identified Acinetobacter baumannii, Pseudomonas aeruginosa, and enterobacteriaceae (Klebsiella pneumoniae, E. coli, etc.) as the pathogens of top priority because of their ability to cause difficult-to-treat life-threatening infections insusceptible to conventional antibiotic therapy. Hence, the severity of the current scenario necessitates the development of a potent therapeutic agent with a smart strategy. Toward this goal herein, we have explored the potency of membrane-active, amino-acid-conjugated polymers (ACPs) to combat notorious Gram-negative pathogens in combination with intrinsically resistant antibiotic rifampicin. The polymers were able to enhance the antibacterial potency of rifampicin against different drug-resistant Gram-negative bacteria by 4–66 fold. The combination, which consisted of glycine-conjugated polymer, ACP-1 (Gly), and rifampicin was rapidly bactericidal in nature. This combination also exhibited significant potency to disrupt the preformed biofilms of drug-resistant strains of P. aeruginosa and E. coli. More importantly, a negligible propensity of resistance development was observed against this combination, whereas a high level of resistance development was observed against the last-resort antibiotic, colistin. Furthermore, ACP-1 (Gly) displayed noticeably good 50% lethal dosage in different administration routes (LD50 (subcutaneous) > 179 mg/kg and LD50 (intraperitoneal) = 100 mg/kg) in a mouse model. Additionally, ACP-1 (Gly) did not show any adverse effect on mouse skin even at 200 mg/kg. Therefore, the results ensured that the ACP-1 (Gly) is suitable for both topical as well as systemic application. Altogether, the results indicated significant promises of the combination for further development as a therapeutic regimen to tackle the outbreak of critical Gram-negative bacteria.

The alarming situation in public healthcare caused by ever‐increasing catastrophe of antimicrobial resistance, recurrent infections, and associated inflammation has accelerated the hunt for novel therapeutics which can address these diverse problems concomitantly. This article introduces a new class of multi‐functional amino acid conjugated small antibacterial molecules (ASAMs) which tackle complicated infections and associated inflammation. These molecules exhibit broad‐spectrum bactericidal activity against multi‐drug‐resistant bacteria. The phenylalanine‐bearing lead molecule (ASAM‐10) tackles bacterial dormant subpopulations, impenetrable biofilms, and intracellular pathogens simultaneously. Importantly, this molecule addresses the problem of toxicity associated with cationic lipopeptides like colistin through the temporal charge switching (cationic to zwitterionic) owing to the degradation of labile ester linkages. However, this does not affect its desired antibacterial action window. The substantial reduction in the overexpression of pro‐inflammatory cytokines (IL‐6, IL‐8, TNF‐α, and IL‐1β) upon treatment of infected macrophages with ASAM‐10 validates its anti‐inflammatory efficacy. Furthermore, bacteria exhibit diminished susceptibility toward resistance development against ASAM‐10 owing to its membrane‐active nature. ASAM‐10 displays significant reduction in bacterial burden (2 Log CFU/g) when administered intraperitoneally in mice for MRSA thigh infection. Overall, this new class of multi‐functional molecules is safe for anticipated advanced therapeutic applications to combat complex bacterial infections and inflammation.

The escalating rise in the population of multidrug‐resistant (MDR) pathogens coupled with their biofilm forming ability has struck the global health as nightmare. Alongwith the threat of aforementioned menace, the sluggish development of new antibiotics and the continuous deterioration of the antibiotic pipeline has stimulated the scientific community toward the search of smart and innovative alternatives. In near future, membrane targeting antimicrobial polymers, inspired from antimicrobial peptides, can stand out significantly to combat against the MDR superbugs. Many of these amphiphilic polymers can form nanoaggregates through self‐assembly with superior and selective antimicrobial efficacy. Additionally, these macromolecular nanoaggregrates can be utilized to engineer smart antibiotic‐delivery system for on‐demand drug‐release, exploiting the infection site's micoenvironment. This strategy substantially increases the local concentration of antibiotics and reduces the associated off‐target toxicity. Furthermore, amphiphilc macromolecules can be utilized to rejuvinate obsolete antibiotics to tackle the drug‐resistant infections. This review article highlights the recent developments in macromolecular architecture to design numerous nanostructures with broad‐spectrum antimicrobial activity, their application in fabricating smart drug delivery systems and their efficacy as antibiotic adjuvants to circumvent antimicrobial resistance. Finally, the current challenges and future prospects are briefly discussed for further exploration and their practical application in clinical settings.