Vancomycin, a natural glycopeptide antibiotic, was used as the antibiotic of last resort for the treatment of multidrug-resistant Gram-positive bacterial infections. However, almost 30 years after its use, resistance to vancomycin was first reported in 1986 in France. This became a major health concern, and alternative treatment strategies were urgently needed. New classes of molecules, including semisynthetic antibacterial compounds and newer generations of the previously used antibiotics, were developed. Semisynthetic derivatives of vancomycin with enhanced binding affinity, membrane disruption ability, and lipid binding properties have exhibited promising results against both Gram-positive and Gram-negative bacteria. Various successful approaches developed to overcome the acquired resistance in Gram-positive bacteria, intrinsic resistance in Gram-negative bacteria, and other forms of noninherited resistance to vancomycin have been discussed in this Perspective.

Combination therapy with membrane-targeting compounds is at the forefront because the bacterial membrane is an attractive target considering its role in various multidrugresistant elements. However, this strategy is crippled by the toxicity associated with these agents. The structural requirements for optimum membrane perturbation and minimum toxicity have not been explored for membrane-targeting antibiotic potentiators or adjuvants. Here, we report the structural influence of different chemical moieties on membrane perturbation, activity, toxicity, and potentiating ability in norspermidine derivatives. It has been shown in this report that weak membrane perturbation, achieved by the incorporation of cyclic hydrophobic moieties, is an effective strategy to design antibiotic adjuvants with negligible in vitro toxicity and activity but good potentiating ability. Aryl or adamantane functionalized derivatives were found to be better resorts as opposed to the acyclic analogues, exhibiting as high as 4096-fold potentiation of multiple classes of antibiotics toward critical Gram-negative superbugs. The mechanism of potentiation was nonspecific, consisting of weak outer-membrane permeabilization, membrane depolarization, and efflux inhibition. This unique concept of "weakly perturbing the membrane" by incorporating cyclic hydrophobic moieties in a chemical design with free amine groups serves as a breakthrough for nontoxic membrane-perturbing adjuvants and has the potential to revitalize the effect of obsolete antibiotics to treat complicated Gram-negative bacterial infections.

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 β-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.

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 broadspectrum antimicrobial agent.

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.