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Schematic of membrane disruptive and non-membrane disruptive bacterial killing mechanisms of AMPs Illustration created with BIORENDER.COM.
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The discovery of antibiotics marked a golden age in the revolution of human medicine. However, decades later, bacterial infections remain a global healthcare threat, and a return to the pre-antibiotic era seems inevitable if stringent measures are not adopted to curb the rapid emergence and spread of multidrug resistance and the indiscriminate use...
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Context 1
... research has been conducted, and is still ongoing, to unveil the MOA of AMPs ( Guilhelmelli et al., 2013;Hancock & Lehrer, 1998;Ulm et al., 2012). Based on their MOA, AMPs can be classified into those that kill through membrane disruptive mechanisms and non-membrane disruptive mechanisms, as illustrated in Figure 3. For the membrane disruptive killing action, AMPs produce microbicidal activity by targeting and disrupting the bacterial plasma-membrane structure, mostly through permeabilization, thus resulting in leakage of intracellular content ( Huang et al., 2010). ...
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Significance
This work showed that a designed cyclic peptide ZY4 exhibits excellent activity against Pseudomonas aeruginosa and Acinetobacter baumannii . ZY4 not only inhibits planktonic growth and biofilm formation but also kills persister cells by permeabilizing bacterial membrane. ZY4 showed low propensity to induce resistance, high stability in...
Antimicrobial peptides have been identified as one of the alternatives to the extensive use of common antibiotics as they show a broad spectrum of activity against human pathogens. Among these is Chionodracine (Cnd), a host-defense peptide isolated from the Antarctic icefish Chionodraco hamatus, which belongs to the family of Piscidins. Previously,...
Citations
... Furthermore, resistance to ciprofloxacin in E. coli varies from 8.4% to a concerning 92.9%, while in K. pneumoniae, it ranges from 4.1 to 79.4% [177]. In contrast, AMPs can have multiple targets or multiple AMPs can act on the same target, thereby effectively minimizing the emergence of bacterial resistance [178]. However, the industrialization of AMPs is challenged by significantly high production costs, estimated at US$50-400 per gram of amino acids for commercial-scale production [167] . ...
Antibiotic resistance is currently one of the most significant threats to global public health and safety. And studies have found that over the next 25 years, 39 million people will die directly and 169 million indirectly due to antibiotic-resistant diseases. Consequently, the development of new types of antimicrobial drugs is urgently needed. Antimicrobial peptides (AMPs) constitute an essential component of the innate immune response in all organisms. They exhibit a distinctive mechanism of action that endows them with a broad spectrum of biological activities, including antimicrobial, antibiofilm, antiviral, and anti-inflammatory effects. However, AMPs also present certain limitations, such as cytotoxicity, susceptibility to protein hydrolysis, and poor pharmacokinetic properties, which have impeded their clinical application. The development of delivery systems can address these challenges by modifying AMP delivery and enabling precise, controlled release at the site of infection or disease. This review offers a comprehensive analysis of the mechanisms of action and biological advantages of AMPs. and systematically evaluate how emerging drug delivery systems, such as nanoparticles and hydrogels, enhance the stability and bioavailability of AMPs, discussing both their strengths and limitations. Moreover, unlike previous reviews, this review highlight the most recent clinically approved AMP-based drugs and those currently in development, emphasizing the key challenges in translating these drugs into clinical practice. With these perspectives, it is hoped that this review will provide some insights into overcoming translational barriers and advancing AMPs drugs into clinical practice.
Graphical Abstract
... continuously [31][32][33][34][35], and are secreted at specific sites in the body [36,37]. These peptides modulate the microbiome and protect the host against infections by inhibiting the growth of microbial cells and orchestrating the host immune response [22,36,[38][39][40]. ...
... These peptides modulate the microbiome and protect the host against infections by inhibiting the growth of microbial cells and orchestrating the host immune response [22,36,[38][39][40]. There are few bacterial mechanisms of resistance against these HDPs [41,42], which demonstrates another advantage over the antibiotics currently used [35]. Biotechnological approaches for the discovery and chemical synthesis of HDPs constitute a new scientific frontier to explore, with the ultimate goal of overcoming the "silent pandemic" of antimicrobial resistance [43]. ...
Porcine β-defensins (pBDs) are cationic peptides that are classically associated with the innate immune system. These molecules yield both antimicrobial and immunomodulatory properties, as evidenced by various in vitro and animal trials. Researchers have revealed that enhancing pBD expression can be achieved through dietary components and gene editing techniques in pigs and porcine cell models. This state-of-the-art review aims to encapsulate the piv-otal findings and progress made in the field of pBD over recent decades, with a specific emphasis on the biological role of pBD in infection control and its usage in clinical trials, thereby offering a new landscape of opportunities for research aimed at identifying prophylactic and therapeutic alternatives for both swine medicine and translational purposes.
... Consequently, they are significant contributors to elevated morbidity, mortality, and healthcare costs, and the number of deaths due to drug resistance is increasing every year [10]. In contrast, antimicrobial peptides (AMPs) exhibit distinct advantages by targeting multiple sites on the plasma membrane and intracellular components of pathogenic bacteria, demonstrating potent efficacy against resistant bacterial strains [11,12], making them promising alternatives to traditional drugs against drug-resistant bacteria. SAAP-148, a novel AMP inspired by the human AMP LL-37, demonstrates broad-spectrum antimicrobial activity and low host cytotoxicity against MDR strains and has undergone clinical trials [13]. ...
Escherichia coli (E. coli) is a zoonotic bacterium widespread in the environment, highly transmissible, and responsible for significant economic losses and millions of cases of illness annually. The rise of multidrug-resistant (MDR) strains has rendered last-line antibiotics such as polymyxin and meropenem ineffective, making the development of new antibiotics urgent. Although D-CONGA-Q7 has broad-spectrum bactericidal activity, its underlying mechanism remains poorly understood. In this study, we used in vitro and in vivo experiments to demonstrate that D-CONGA-Q7 effectively kills both antibiotic-sensitive and multidrug-resistant strains of E. coli. D-CONGA-Q7 disrupts the cell membranes of Gram-negative bacteria, and the treatment of E. coli strain LN175 with D-CONGA-Q7 resulted in a significant up-regulation of the Mlac gene, suggesting that D-CONGA-Q7 may interact with phospholipids in the cell membrane. Furthermore, in treating K88-induced bacterial enteritis in the small intestine, D-CONGA-Q7 significantly reduced intestinal inflammation. In conclusion, this study provides a novel approach to combat drug-resistant E. coli.
... This phenomenon is particularly concerning in the context of hospital-acquired infections and food security, necessitating ongoing research into new antibacterial compounds, including antimicrobial peptides (AMPs). AMPs, in particular, have demonstrated a wide range of mechanisms against bacteria and fungi, from pore formation in microbial membranes to modulation of the host immune response [5,6,7,8]. These properties make them especially promising in combating resistant infections. ...
The mandacaru is a cactus species complex widely known in Brazil, with extensive applications in medicinal, food, and agricultural fields. Although it is used medicinally, by traditional populations, to treat several diseases, knowledge about its biomolecules of biotechnological potential is still limited, specifically regarding antimicrobial and healing properties. The bacterial resistance to conventional antibiotics presents a significant challenge in modern medicine. In light of this scenario, the bioprospecting of mandacaru for biotechnological applications as an antimicrobial begins as a new and imperative research area. In this study, transcriptomic data from three Cereus species ( C. fernambucensis , C. hildmannianus , and C. jamacaru ) were combined with bioinformatic approaches, including protein modeling, molecular docking, and molecular dynamics simulations, to identify proteins with therapeutic potential for treating wound infections. Our findings highlighted peptides with particularly promising antimicrobial agents, demonstrating efficacy against a range of pathogens, including Gram-positive and Gram-negative bacteria, as well as fungi. Those peptides showed strong interactions with the STD and Na ligands, though the STD ligand emerged as the most likely candidate for enhancing antimicrobial activity. Molecular dynamics revealed that while CF15 exhibited limited stability, CF267, CF48, CH167, and CH176 displayed superior stability, positioning it as the most promising candidate for further investigation. Future work will focus on synthesizing them and evaluating its antimicrobial properties through in vitro and in vivo analyses, with the goal of developing it into a potent therapeutic agent.
... They are less likely to trigger resistance in bacteria, act much faster, and can work against a wider range of bacteria, fungi, and enveloped viruses. This makes them particularly effective against even those strains of bacteria that are resistant to multiple antibiotics (23,24). AMP exhibit potent bactericidal activity against pathogens affecting the respiratory tract, intestine, and udder, such as Mannheimia haemolytica, Histophilus somni, Pasteurella multocida, Escherichia coli, and Staphylococcus aureus (25)(26)(27)(28)(29). Epigenetic pathways, including DNA methylation and histone modification, play key roles in regulating the expression and production of AMP (30,31). ...
Introduction
Maternal nutrition during pregnancy critically influences offspring development and immune function. One-carbon metabolites (OCM) are epigenetic modifiers that may modulate antimicrobial peptide (AMP) expression, which is vital for innate immunity. This study investigated the effects of maternal nutrient restriction and OCM supplementation on mRNA expression of AMP in fetal and maternal lung, mammary gland, and small intestine of beef cattle.
Methods
Twenty-nine crossbred Angus beef heifers were synchronized for estrus and artificially inseminated. They were assigned to one of four treatments in a 2 × 2 factorial design: nutritional plane [control (CON) vs. restricted (RES)] and OCM supplementation [without OCM (−OCM) or with OCM (+OCM)]. Heifers on the CON diet were fed to gain 0.45 kg/day, while RES heifers were fed to lose 0.23 kg/day. Treatments were applied from day 0 to 63 of gestation, after which all heifers were fed a common diet to gain 0.45 kg/day until day 161 of gestation, when samples were collected. Quantitative RT-qPCR was used to assess mRNA expression of AMP.
Results
Nutritional plane had no effect (p ≥ 0.24) on mRNA expression of AMP in either the fetus or dams. However, the mRNA expression of cathelicidin5 (CATHL5; p = 0.07) and bovine neutrophil β-defensin5 (BNBD5; p = 0.07) in the fetal lung and mammary gland, respectively, was lower in the +OCM groups compared to the −OCM groups. In the maternal small intestine, the expression of enteric β-defensin (EBD) was lower (p = 0.01) in the +OCM groups compared to the −OCM groups. Additionally, in the maternal lung, there was a tendency (p = 0.06) for an interaction in CATHL5 mRNA expression, with the RES + OCM group showing greater expression compared to the CON + OCM (p = 0.07) and RES − OCM (p = 0.08) groups.
Discussion
Our findings suggest that while restricted maternal nutrition did not affect mRNA expression of AMP, OCM supplementation modulated AMP expression in both fetal and maternal tissues. Further research is needed to elucidate the mechanisms underlying OCM’s impact on AMP expression.
... Antimicrobial peptides (AMPs) are an important substitute for antibiotics that affect a wide range of microbes. AMPs offer a potential avenue to fight against MDR, XDR, and Col-RAB through a variety of mechanisms [157,158]. Numerous studies on AMPs suggest that AMPs, either alone or in combination with colistin, show effectiveness against MDR, XDR, and Col-RAB. Peptides such as Esc , melittin, indolicidin, mastoparan, Ω76, NuriPep 1653, Cec4, 2K4L, LS-sarcotoxin, and LS-stomoxyn have demonstrated effectiveness against A. baumannii [159][160][161][162][163][164][165]. ...
The emergence of antibiotic-resistant Acinetobacter baumannii (A. baumannii) is a pressing threat in clinical settings. Colistin is currently a widely used treatment for multidrug-resistant A. baumannii, serving as the last line of defense. However, reports of colistin-resistant strains of A. baumannii have emerged, underscoring the urgent need to develop alternative medications to combat these serious pathogens. To resist colistin, A. baumannii has developed several mechanisms. These include the loss of outer membrane lipopolysaccharides (LPSs) due to mutation of LPS biosynthetic genes, modification of lipid A (a constituent of LPSs) structure through the addition of phosphoethanolamine (PEtN) moieties to the lipid A component by overexpression of chromosomal pmrCAB operon genes and eptA gene, or acquisition of plasmid-encoded mcr genes through horizontal gene transfer. Other resistance mechanisms involve alterations of outer membrane permeability through porins, the expulsion of colistin by efflux pumps, and heteroresistance. In response to the rising threat of colistin-resistant A. baumannii, researchers have developed various treatment strategies, including antibiotic combination therapy, adjuvants to potentiate antibiotic activity, repurposing existing drugs, antimicrobial peptides, nanotechnology, photodynamic therapy, CRISPR/Cas, and phage therapy. While many of these strategies have shown promise in vitro and in vivo, further clinical trials are necessary to ensure their efficacy and widen their clinical applications. Ongoing research is essential for identifying the most effective therapeutic strategies to manage colistin-resistant A. baumannii. This review explores the genetic mechanisms underlying colistin resistance and assesses potential treatment options for this challenging pathogen.
... 10 AMPs offer several advantages, including potent, rapid antimicrobial activity, a lower likelihood of developing resistance, and lethality against slow-growing or metabolically inactive microorganisms (e.g., persisters). 11,12 Thus, AMPs hold considerable potential for the development of novel antimicrobial drugs. ...
... 11 TC-33 contains 5 glutamates, which reduce its cationicity and likely contribute to its poor antimicrobial activity. 12,17 In addition, AMPs with short primary sequences show advantages including reduced cost of peptide synthesis, good permeability, high bioavailability, and low immunogenicity. We thus initially designed a smaller peptide, termed TC-LAE-18, by removing eight residues from the N-terminus and seven from the C-terminus of TC-33 (Table 1). ...
... 49 Structure−activity relationship studies have elucidated the mechanisms by which AMP functions, primarily involving their binding to and penetration of bacterial cell membranes, leading to membrane lysis and cell death. 12,50 Initial bacterial membrane binding is predominantly driven by electrostatic interactions, while membrane permeation is facilitated by the hydrophobic characteristics of AMPs. The number of cationic residues and the overall net charge are crucial for antimicrobial potential because they enhance initial electrostatic interactions with negatively charged bacterial membrane components. ...
The number of cationic residues and net charge are critical for the activity of antimicrobial peptides (AMPs) due to their role in facilitating initial electrostatic interactions with negatively charged bacterial membranes. A cathelicidin AMP (TC-33) has been identified from the Chinese tree shrew in our previous work, which exhibited weak antimicrobial activity, likely due to its moderately cationic nature. In the current study, based on TC-33, we designed a novel AMP by peptide truncation and Glu substitutions to increase its net cationic charge from +4 to +8. The resulting peptide, TC-LAR-18, showed 4–128-fold enhanced antimicrobial activity relative to TC-33 without causing hemolysis and cytotoxicity within 100 μg/mL. TC-LAR-18 effectively eliminated both planktonic and biofilm-associated bacteria, demonstrating rapid bactericidal effects due to its ability to quickly penetrate and disrupt bacterial cell membranes with a low propensity to induce resistance. Notably, TC-LAR-18 provided substantial protection against skin bacterial infection in mice, underscoring its therapeutic potential. These findings not only highlight the importance of positively charged residues for the antibacterial activity of AMPs but also present a useful drug candidate for combating multidrug-resistant bacteria.
... However, the emergence of bacterial resistance to long term and broad-spectrum antibiotics becomes a serious problem for clinical management of infections and for a wide range of consumers who have the potential risk of acquired antibiotic resistance (Hiltunen et al. 2017). The advantage of using AMPs is that they act on multiple targets of the pathogenic bacteria plasma membrane and have a potent activity against antibiotic resistant bacteria (Mwangi et al. 2019). ...
Antimicrobial and antitumor activities of bovine colostrum peptide and its synthesized analogue were carried out. The peptide was produced by standard solid phase synthesis followed by purification by high-performance liquid chromatography. Peptide purity and primary structure were confirmed by MALDI and ESI MS. It was found that the synthesized peptide with ACSAG amino acid sequence and a molecular weight of 430.2332 was an analogue of the natural one. The synthesized peptide had a high hydrophilic value and isoelectric point of 5.22. The obtained data theoretically confirm that the studied peptide belongs to a class of antimicrobial peptides. It was experimentally established that both natural and synthesized peptides had antimicrobial activity against E. coli ATCC 25922, P. aeruginosa 27/99 and B. subtilis АТСС 6633, antifungal and anti-tumor activity against C6 cells. After 48 h there was a significant 50% decrease in the tumor cells population at the concentration of the natural peptide of 365.5±3.8 mg.ml-1, and the synthesized peptide concentration of 312.7±3.5 mg.ml-1 in the nutrient medium. This synthesized peptide has a greater biological activity and can be effective at lower concentrations, than the natural one.
... Cationic antimicrobial peptides (AMPs), as a new class of antimicrobial agents, have attracted tremendous attention and been exploited to combat MDR bacteria in the last decades (13)(14)(15)(16)(17). Unlike conventional antibiotics, AMPs act their biocidal activities through membrane perturbation caused by electrostatic and hydrophobic interactions owing to their structural characteristic of cationic amphiphilicity, and this distinctive antimicrobial mechanism displayed a low propensity to develop bacterial resistance (18)(19)(20)(21). ...
ESKAPE pathogens are a panel of most recalcitrant bacteria that could “escape” the treatment of antibiotics and exhibit high incidence of drug resistance. The emergence of multidrug-resistant (MDR) ESKAPE pathogens (particularly Gram-negative bacteria) accounts for high risk of mortality and increased resource utilization in health care. Worse still, there has been no new class of antibiotics approved for exterminating the Gram-negative bacteria for more than 50 years. Therefore, it is urgent to develop novel antibacterial agents with low resistance and potent killing efficacy against Gram-negative ESKAPE pathogens. Herein, we present a class of fluoropolymers by mimicking the amphiphilicity of cationic antimicrobial peptides. Our optimal fluoroamphiphilic polymer (PD 45 HF 5 ) displayed selective antimicrobial ability for all MDR Gram-negative ESAKPE pathogens, low resistance, high in vitro cell selectivity, and in vivo curative efficacy. These findings implied great potential of fluoroamphiphilic cationic polymers as promising antibacterial agents against MDR Gram-negative ESKAPE bacteria and alleviating antibiotic resistance.
... The most known cause of AMR is the inappropriate use of antibiotics for therapeutic and non-therapeutic purposes. However, it should be noted that not only has the undiscriminating use of antimicrobials promoted AMR but horizontal gene transfer (HGT) is also key in the spread of antibiotic resistance genes (ARGs) between bacteria from different environments, which encourages resistance [3], as this provides organisms with traits for greater environmental adaptability and survival owing to the presence of antibiotics in different niches [4], thus reducing therapeutic options and increasing the problem. ...
... Consequently, Cui and cols. synthesized derivatives (2)(3)(4)(5)(6)(7)(8)(9)(10)(11) of this compound, observing that compounds 9, 7 (substituted aryl), and 11 (substituted aromatic heterocycle) showed the inhibition of NDM-1 at 0.11, 0.06, and 0.46 μM, respectively, when alkyl chain elongation was performed in 9 and 8 and pyridine derivatives were used in 11 [51]. Compound 8 has been observed to exhibit cytotoxic activity. ...
Currently, antimicrobial resistance (AMR) is a serious health problem in the world, mainly because of the rapid spread of multidrug-resistant (MDR) bacteria. These include bacteria that produce β-lactamases, which confer resistance to β-lactams, the antibiotics with the most prescriptions in the world. Carbapenems are particularly noteworthy because they are considered the ultimate therapeutic option for MDR bacteria. However, this group of antibiotics can also be hydrolyzed by β-lactamases, including metallo-β-lactamases (MBLs), which have one or two zinc ions (Zn2+) on the active site and are resistant to common inhibitors of serine β-lactamases, such as clavulanic acid, sulbactam, tazobactam, and avibactam. Therefore, the design of inhibitors against MBLs has been directed toward various compounds, with groups such as nitrogen, thiols, and metal-binding carboxylates, or compounds such as bicyclic boronates that mimic hydrolysis intermediates. Other compounds, such as dipicolinic acid and aspergillomarasmin A, have also been shown to inhibit MBLs by chelating Zn2+. In fact, recent inhibitors are based on Zn2+ chelation, which is an important factor in the mechanism of action of most MBL inhibitors. Therefore, in this review, we analyzed the current strategies for the design and mechanism of action of metal-ion-binding inhibitors that combat MDR bacteria.
