The Development of Third-Generation Tetracycline Antibiotics and New Perspectives

The tetracycline antibiotic class has acquired new valuable members due to the optimisation of the chemical structure. The first modern tetracycline introduced into therapy was tigecycline, followed by omadacycline, eravacycline, and sarecycline (the third generation). Structural and physicochemical key elements which led to the discovery of modern tetracyclines are approached. Thus, several chemical subgroups are distinguished, such as glycylcyclines, aminomethylcyclines, and fluorocyclines, which have excellent development potential. The antibacterial spectrum comprises several resistant bacteria, including those resistant to old tetracyclines. Sarecycline, a narrow-spectrum tetracycline, is notable for being very effective against Cutinebacterium acnes. The mechanism of antibacterial action from the perspective of the new compound is approached. Several severe bacterial infections are treated with tigecycline, omadacycline, and eravacycline (with parenteral or oral formulations). In addition, sarecycline is very useful in treating acne vulgaris. Tetracyclines also have other non-antibiotic properties that require in-depth studies, such as the anti-inflammatory effect effect of sarecycline. The main side effects of modern tetracyclines are described in accordance with published clinical studies. Undoubtedly, this class of antibiotics continues to arouse the interest of researchers. As a result, new derivatives are developed and studied primarily for the antibiotic effect and other biological effects.

Biological Effects of Quinolones: A Family of Broad-Spectrum Antimicrobial Agents

Broad antibacterial spectrum, high oral bioavailability and excellent tissue penetration combined with safety and few, yet rare, unwanted effects, have made the quinolones class of antimicrobials one of the most used in inpatients and outpatients. Initially discovered during the search for improved chloroquine-derivative molecules with increased anti-malarial activity, today the quinolones, intended as antimicrobials, comprehend four generations that progressively have been extending antimicrobial spectrum and clinical use. The quinolone class of antimicrobials exerts its antimicrobial actions through inhibiting DNA gyrase and Topoisomerase IV that in turn inhibits synthesis of DNA and RNA. Good distribution through different tissues and organs to treat Gram-positive and Gram-negative bacteria have made quinolones a good choice to treat disease in both humans and animals. The extensive use of quinolones, in both human health and in the veterinary field, has induced a rise of resistance and menace with leaving the quinolones family ineffective to treat infections. This review revises the evolution of quinolones structures, biological activity, and the clinical importance of this evolving family. Next, updated information regarding the mechanism of antimicrobial activity is revised. The veterinary use of quinolones in animal productions is also considered for its environmental role in spreading resistance. Finally, considerations for the use of quinolones in human and veterinary medicine are discussed.

Characteristics of Two Crustins from Alvinocaris longirostris in Hydrothermal Vents

Crustins are widely distributed among different crustacean groups. They are characterized by a whey acidic protein (WAP) domain, and most examined Crustins show activity against Gram-positive bacteria. This study reports two Crustins, Al-crus 3 and Al-crus 7, from hydrothermal vent shrimp, Alvinocaris longirostris. Al-crus 3 and Al-crus 7 belong to Crustin Type IIa, with a similarity of about 51% at amino acid level. Antibacterial assays showed that Al-crus 3 mainly displayed activity against Gram-positive bacteria with MIC50 values of 10–25 μM. However, Al-crus 7 not only displayed activity against Gram-positive bacteria but also against Gram-negative bacteria Imipenem-resistant Acinetobacter baumannii, in a sensitive manner. Notably, in the effective antibacterial spectrum, Methicillin-sensitive Staphylococcus aureus, Escherichia coli (ESBLs) and Imipenem-resistant A. baumannii were drug-resistant pathogens. Narrowing down the sequence to the WAP domain, Al-crusWAP 3 and Al-crusWAP 7 demonstrated antibacterial activities but were weak. Additionally, the effects on bacteria did not significantly change after they were maintained at room temperature for 48 h. This indicated that Al-crus 3 and Al-crus 7 were relatively stable and convenient for transportation. Altogether, this study reported two new Crustins with specific characteristics. In particular, Al-crus 7 inhibited Gram-negative imipenem-resistant A. baumannii.

Ceftazidime-avibactam

Ceftazidime is a 3rd generation cephalosporin active against Pseudomonas aeruginosa. Avibactam is an inhibitor of class A, C and some class D β-lactamases. The antibacterial spectrum of ceftazidime-avibactam covers 95% of P. aeruginosa isolates and >99% of enterobacteria, including strains carrying extended-spectrum β-lactamases (ESBLs). Selection of resistant mutants in Klebsiella pneumoniae and Enterobacter cloacae strains producing KPC-3 or KPC-2 after exposure to ceftazidime-avibactam has been described by the appearance of one or more amino acid changes in the Ω-loop of the β-lactamase. These strains usually regain susceptibility to meropenem. There is evidence of a shorter multidrug-resistant organisms colonization period in patients treated with this antimicrobial, which could be beneficial in the treatment of infections caused by bacteria carrying ESBLs or carbapenemases.

Research Progress on Antibacterial Activities and Mechanisms of Natural Alkaloids: A Review

Alkaloids are nitrogen-containing heterocyclic compounds typically isolated from plants. They represent one of the most important types of natural products because of their large number and structural diversity and complexity. Based on their chemical core structures, alkaloids are classified as isoquinolines, quinolines, indoles, piperidine alkaloids, etc. In-depth analyses of alkaloids have revealed their antibacterial activities. To date, due to the widespread use of antibiotics, the problem of drug-resistant bacterial infections has been gradually increasing, which severely affects the clinical efficacy of antibacterial therapies and patient safety. Therefore, significant research efforts are focused on alkaloids because they represent a potentially new type of natural antibiotic with a wide antibacterial spectrum, rare adverse reactions, and a low tendency to produce drug resistance. Their main antibacterial mechanisms include inhibition of bacterial cell wall synthesis, change in cell membrane permeability, inhibition of bacterial metabolism, and inhibition of nucleic acid and protein synthesis. This article reviews recent reports about the chemical structures and the antibacterial activities and mechanisms of alkaloids. The purpose is to solve the problem of bacterial resistance and to provide a certain theoretical basis and research ideas for the development of new antibacterial drugs.

Use of Linezolid in the treatment of surgical infectious complications under antibiotic resistance

Linezolid – a first representative of the new class of synthetic antibiotics oxazolidones. Its antibacterial spectrum includes Gram-positive microorganisms, including multi-resistant strains. Its unique mechanism of action conditions absence of cross-resistance with other antibiotics. This drug is presented in peroral and parenteral forms. Unlike vancomycin, it has optimal pharmacokinetic profile. Linezolid was approved by Food and Drug Administration (FDA) in 2000 for the treatment of the following diseases: hospital- and community-acquired pneumonia, skin and soft tissue infections with or without complications caused by Gram-positive bacteria, vancomycin-resistant enterococci and pneumococcal meningitis, caused by penicillin-resistant Streptococcus pneumoniae.

Minocycline and doxycycline: More Than Antibiotics.

: Minocycline and doxycycline both are second-generation tetracycline antibiotic with similar chemical structures and comparable antibacterial spectrum. Minocycline has also emerged as the tetracycline of choice for multidrug-resistant Acinetobacter baumannii infections, although doxycycline has also shown the activity. Minocycline showed promising results in experimental neurology, which was due to its highly lipophilic nature. It is clinically safe and effective adjunct to antipsychotic medications.The objective of the current review is to provide clinical and preclinical, non-antibiotic uses of minocycline as well as doxycycline.Relevant literature covers antibiotic actions but is more specifically concerned with the non-antibiotic biological aspect of the tetracyclines. Non-antibiotic biological effects for both the antibiotics were identified through searching relevant databases including: PubMed, Scopus, and Web of Science up to 2020, using the keywords ‘minocycline and doxycycline’. Anti-inflammatory, anti-oxidant, anti-apoptotic neuroprotective, immunomodulatory and number of other non-antibiotic effects were compiled for minocycline and doxycycline.