AI-Designed Molecules Show Potent Activity Against Resistant Bacteria

Design, synthesis and structure–activity relationships of novel N11-, C12- and C13-substituted 15-membered homo-aza-clarithromycin derivatives against various resistant bacteria

A novel series of 4''-carbamates of 6,11-di-O-methylerythromycin A were synthesized and evaluated. These compounds have significant antibacterial activity against Gram-positive pathogens, including erythromycin-resistant but methicillin-susceptible Staphylococcus aureus, erythromycin-resistant and methicillin-resistant Staphylococcus aureus, erythromycin-resistant Streptococcus pneumoniae and Gram-negative pathogens, such as Haemophilus influenzae To our surprise, most of the derivatives tested had potent activity against most resistant bacteria. Among these, compounds 10u, 10v, 10w and 10y were found to have potent activity against most susceptible and resistant bacteria. In particular, compound 10y exhibited excellent antibacterial activity in comparison to others.

Minocycline (7-dimethylamino-6-demethyl-6-deoxytetracycline) is a new semisynthetic tetracycline with potent activity against tetracycline-susceptible bacterial pathogens and unique activity against tetracycline-resistant staphylococci. Studies to determine the basis for this unique activity showed that, whereas tetracycline-resistant staphylococci took up less (3)H-tetracycline than the susceptible cells, both the tetracycline-resistant and -susceptible cells accumulated equivalent amounts of (14)C-minocycline. In contrast, tetracycline-resistant Escherichia coli cells were relatively resistant to minocycline and accumulated less of both drugs than did the susceptible organisms. It is proposed that minocycline is effective against tetracycline-resistant staphylococci because of its ability to penetrate the cells sufficiently to reach inhibiting concentrations at sensitive reaction sites.

Honey has potent activity against both antibiotic-sensitive and -resistant bacteria, and is an interesting agent for topical antimicrobial application to wounds. As honey is diluted by wound exudate, rapid bactericidal activity up to high dilution is a prerequisite for its successful application. We investigated the kinetics of the killing of antibiotic-resistant bacteria by RS honey, the source for the production of Revamil® medical-grade honey, and we aimed to enhance the rapid bactericidal activity of RS honey by enrichment with its endogenous compounds or the addition of antimicrobial peptides (AMPs). RS honey killed antibiotic-resistant isolates of Pseudomonas aeruginosa, Staphylococcus epidermidis, Enterococcus faecium, and Burkholderia cepacia within 2 h, but lacked such rapid activity against methicillin-resistant S. aureus (MRSA) and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. It was not feasible to enhance the rapid activity of RS honey by enrichment with endogenous compounds, but RS honey enriched with 75 μM of the synthetic peptide Bactericidal Peptide 2 (BP2) showed rapid bactericidal activity against all species tested, including MRSA and ESBL E. coli, at up to 10–20-fold dilution. RS honey enriched with BP2 rapidly killed all bacteria tested and had a broader spectrum of bactericidal activity than either BP2 or honey alone.

Semisynthetic derivatives of the clinically useful aminoglycosides tobramycin and amikacin were prepared by selectively modifying their 6'' positions with a variety of hydrogen bond donors and acceptors. Their binding to the rRNA A-site was probed using an in vitro FRET-based assay, and their antibacterial activities against several resistant strains (e.g., Pseudomonas aeruginosa, Klebsiella pneumonia, MRSA) were quantified by determining minimum inhibitory concentrations (MICs). The most potent derivatives were evaluated for their eukaryotic cytotoxicity. Most analogues displayed higher affinity for the bacterial A-site than the parent compounds. Although most tobramycin analogues exhibited no improvement in antibacterial activity, several amikacin analogues showed potent and broad-spectrum antibacterial activity against resistant bacteria. Derivatives tested for eukaryotic cytotoxicity exhibited minimal toxicity, similar to the parent compounds.

An optimized analog of antimicrobial peptide Jelleine-1 shows enhanced antimicrobial activity against multidrug resistant P.aeruginosa and negligible toxicity invitro and invivo.

This minireview contains a compendium of bacteriocin or bacteriocin-like proteins produced from Brevibacillus laterosporus that can inhibit the growth of drug resistant bacteria. A good number of bacterial secondary metabolites/ bacteriocin/ bacteriocin-like proteins are reported to have anti-drug resistant bacteria activity or anti-cancer activity comparable to the existing chemical synthesis antimicrobial drugs or sometimes even better. Information regarding the mode of action of bacteriocin leads to insight into their activity relationship and potency. A further well defined strategy is required to exploit these active molecules used as anti-drug resistant bacteria drugs.

The total synthesis of two key analogues of vancomycin containing single-atom exchanges in the binding pocket (residue 4 amidine and thioamide) are disclosed as well as their peripherally modified (4-chlorobiphenyl)methyl (CBP) derivatives. Their assessment indicates that combined pocket amidine and CBP peripherally modified analogues exhibit a remarkable spectrum of antimicrobial activity (VSSA, MRSA, VanA and VanB VRE) and impressive potencies (MIC = 0.06–0.005 μg/mL) against both vancomycin-sensitive and -resistant bacteria and likely benefit from two independent and synergistic mechanisms of action. Like vancomycin, such analogues are likely to display especially durable antibiotic activity not prone to rapidly acquired clinical resistance.

The increased resistance of glycopeptide based antibiotics has become a serious problem for the chemotherapy of infections triggered by resistant Gram-positive bacteria. This has motivated the urgent sincere efforts to develop potent glycopeptide-based antibiotics in both academy and industry research laboratories. Understanding of the mechanism of action of natural and modified glycopeptides is considered as the basis for the rational design of compounds with valuable properties to achieve the fundamental results. Several hydrophobic glycopeptide analogues active against resistant strains were developed during the last two decades. Three drugs, namely, oritavancin, telavancin and dalbavancin were approved by FDA in 2013-2014. It was found that hydrophobic derivatives act through different mechanisms without binding with the modified target of resistant bacteria. Types: Different types of chemical modifications led to several glycopeptide analogues active against Gram-negative bacteria as advocated by in vitro studies or demonstrating potent antiviral activity in the cell models. A new class of glycopeptide antibiotics with potent activity against sensitive and resistant bacterial strains has been recently reported with the aim to overcome the resistance, however, there are a lot of obscure problems in the complete understanding of their mechanisms of actions. In this review, we summarized the achievements of synthetic methods devoted to the construction of new polycyclic glycopeptide antibiotics and described the studies related to their mechanism of actions.

The resistance developed by life-threatening bacteria toward conventional antibiotics has become a major concern in public health. To combat antibiotic resistance, there has been a significant interest in the development of antimicrobial cationic polymers due to the ease of synthesis and low manufacturing cost compared to host-defense peptides (HDPs). Herein, we report the design and synthesis of amphiphilic polycarbonates containing primary amino groups. These polymers exhibit potent antimicrobial activity and excellent selectivity to Gram-positive bacteria, including multidrug resistant pathogens. Fluorescence and TEM studies suggest that these polymers are likely to kill bacteria by disrupting bacterial membranes. These polymers also show low tendency to elicit resistance in bacteria. Their further development may lead to new antimicrobial agents combating drug-resistance.

Given the alarming incidence of antibiotic resistance in bacteria of medical importance and multiple side effects associated with the modern day chemotherapeutics, there is a constant need for new and effective therapeutic agents that could be easily extracted from our daily used Nepalese culinary. To study the antibacterial and antioxidant activity of common spices, locally available  Clove (Eugenia caryophyllus), Cinnamon (Cinnamomum zylancium), Cumin (Cumin cyminum) and Timur (Zanthoxylum alatum) were subjected to cold extraction using ethanol and was assayed through agar well diffusion method and DPPH radical scavenging activity for different concentration gradient(100 to 500 µg). Zanthoxylum and Eugenia have showed potent antimicrobial activity against Proteus vulgaris and Pseudomonas aeruginosa followed by Cinnamomum and Cumin against Pseudomonas aeruginosa. All the extracts showed effective antimicrobial activity against gram positive and gram negative bacteria, however Escherichia coli remains ineffective towards any of the concentration of spices. DPPH radical scavenging activity showed effective antioxidant activity of the spices in the following order: Eugenia (93.84%) > Cumin (90.4%), Zanthoxylum (88.73%) > Cinnamomum (87.23%). Hence, our present study demonstrated that the ethanolic extract of different spices, Eugenia being the most effective, possess potent antibacterial and antioxidant activity and can be further analyzed for antimicrobial therapeutics and pharmacological evaluation.   Key words: 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, Eugenia, Zanthoxylum, Cinnamon, Cumin.

Nontypeable Haemophilus influenzae (NTHi), an important human respiratory pathogen, frequently causes biofilm infections. Currently, resistance of bacteria within the biofilm to conventional antimicrobials poses a major obstacle to effective medical treatment on a global scale. Novel agents that are effective against NTHi biofilm are therefore urgently required. In this study, a series of natural and synthetic chalcones with various chemical substituents were evaluated in vitro for their antibiofilm activities against strong biofilm-forming strains of NTHi. Of the test chalcones, 3-hydroxychalcone (chalcone 8) exhibited the most potent inhibitory activity, its mean minimum biofilm inhibitory concentration (MBIC50 ) being 16 μg/mL (71.35 μM), or approximately sixfold more active than the reference drug, azithromycin (MBIC50 419.68 μM). The inhibitory activity of chalcone 8, which is a chemically modified chalcone, appeared to be superior to those of the natural chalcones tested. Significantly, chalcone 8 inhibited biofilm formation by all studied NTHi strains, indicating that the antibiofilm activities of this compound occur across multiple strong-biofilm forming NTHi isolates of different clinical origins. According to antimicrobial and growth curve assays, chalcone 8 at concentrations that decreased biofilm formation did not affect growth of NTHi, suggesting the biofilm inhibitory effect of chalcone 8 is non-antimicrobial. In terms of structure-activity relationship, the possible substituent on the chalcone backbone required for antibiofilm activity is discussed. These findings indicate that 3-hydroxychalcone (chalcone 8) has powerful antibiofilm activity and suggest the potential application of chalcone 8 as a new therapeutic agent for control of NTHi biofilm-associated infections.

Synthesis and antibacterial activity of novel 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs

FQs are some of the most widely prescribed antimicrobial agents. Of the total sales of $42 billion from antibiotics worldwide in 2009, FQs represented 17 % of the market, generating $7 billion in global sales (Furiex Pharmaceuticals; http://www.furiex.com). A detailed discussion of structure–activity relationships is beyond the scope of this chapter, but these agents have undergone several iterations, or “generations,” which have consisted of structural modifications to improve potency and spectrum of activity. The classification system of quinolones, from first to fourth generation, is based on the improving spectrum of antibacterial activity and potency against pneumococci and anaerobic organisms and is more of a practical classification system for clinical use [1]. The first generation quinolone upon which all subsequent derivatives are based is nalidixic acid (Fig. 16.1), which was isolated as a by-product during chloroquine synthesis [2]. Nalidixic acid actually is a naphthyridone based on the presence of a nitrogen atom at position 8, whereas quinolones generally have a carbon atom at this position. Second generation drugs, all of which have a fluorine at position 6 of the quinolone nucleus (hence the term “fluoroquinolone”), include norfloxacin, ciprofloxacin, enoxacin, ofloxacin, and pefloxacin. These drugs have added antimicrobial activity versus aerobic Gram-positive bacteria and better activity against Gram-negative bacteria compared to the first-generation drugs, but lack activity against anaerobic bacteria [1]. Third generation agents have even greater activity versus Gram-positive bacteria, especially pneumococci, plus good potency against anaerobic bacteria, and include sparfloxacin, grepafloxacin, temafloxacin, and levofloxacin. Garenoxacin (not US FDA approved), gemifloxacin, gatifloxacin, moxifloxacin, and trovafloxacin (discontinued) are considered fourth generation agents, with even greater activity against pneumococci and anaerobes [1]. FQs are widely used in ophthalmology, and the newest and first developed specifically for topical ophthalmologic use is besifloxacin, which is approved for the treatment of bacterial conjunctivitis. Besifloxacin has a C-8 chlorine substituent and thus is a chloro-fluoroquinolone. It has dual-targeting activity versus topoisomerase IV and DNA gyrase (topoisomerase II), resulting in increased potency and a decreased chance of the emergence of bacterial resistance [3]. Tosufloxacin and sitafloxacin are approved for clinical use in Japan. Sitafloxacin has been shown to have favorable susceptibility rates among most bacteria tested (excluding methicillin-resistant Staphylococcus aureus [MRSA] and Enterococcus faecium), non-inferiority to levofloxacin and tosufloxacin, and a low propensity to cause resistance in Streptococcus pneumoniae [4].

Development of eco-friendly synthetic methods has resulted in the production of biocompatible Ag NPs for applications in medical sector. To overcome the prevailing antibiotic resistance in bacteria, Ag NPs are being extensively researched over the past few years due to their broad spectrum and robust antimicrobial properties. Silver nanoparticles are also being studied widely in advanced anticancer therapy as an alternative anticancer agent to combat cancer in an effective manner. Keeping this backdrop in consideration, this review aims to provide an extensive coverage of the recent progresses in the green synthesis of Ag NPs specifically using plant derived reducing agents such phytochemicals and numerous other biopolymers. Current development in antimicrobial activity of Ag NPs against various pathogens has been deliberated at length. Recent advances in potent anticancer activity of the biogenic Ag NPs against various cancerous cell lines has also been discussed in detail. Mechanistic details of the synthesis of Ag NPs, their anticancer and antimicrobial action has also been highlighted.