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Antibiotics which Target the Cell Wall:
Beta-lactam antibiotics are the most widely used class of drugs for the treatment of bacterial infections. They include penicillin and its derivatives, such as methicillin and amoxicillin. The beta-lactam ring portion of the antibiotic targets the penicillin-binding proteins (PBP), found in the bacterial cell membrane, which function in the synthesis of the cell wall. Binding of the antibiotic to the PBPs prevents the PBPs from performing their essential role and results in the death of the bacterial cell.
Gram positive bacteria acquire resistance to beta-lactam antibiotics through the production of a protein called PBP2a, which is able to avoid the inhibitory effects of the antibiotics. This is the mechanism by which MRSA is able to persist despite treatment with multiple beta-lactam antibiotics.
The genes for beta-lactamase enzymes are probably the most international in distribution: random mutations of the genes encoding the enzymes have given rise to modified catalysts with increasingly extended spectra of resistance. The archetypical plasmid-encoded beta-lactamase, TEM, has spawned a huge tribe of related enzyme families, providing ample proof this adaptability. The beta-lactamase genes are ancient and have been found in remote and desolate environments, which implied that novel beta-lactamases with altered substrate ranges occur in the environment. (Davies, “origins and Evolution of Antibiotic Resistance” Microbiology and Molecualr Biology Reviews, 2010, p. 417-433).
–Penicillin: was discovered by Alexander Fleming in 1928 after he noticed that an old culture plate (contaminated with Penicillium notatum) grew a mould that prevented the growth of S. aureus. He experimented with different moulds to better understand this effect and determined that not all moulds produced the antimicrobial component detected on this plate. While he failed to isolate the active molecule itself, he named it penicillin. In 1940 Howard Florey and Ernst Chain published a paper that described a purification technique for penicillin and in 1945 penicillin was available for limited use in human treatment. See Mudgill
Even before the discovery of penicillin by Alexander Fleming in 1928, mould had
been recognised as having medicinal properties. In ancient Egypt, Greece, China and
Rome topical applications of mouldy bread were used to treat infections. In 1870, Sir
John Scott Burdon-Sanderson described mould covered culture fluid as being capable
of inhibiting bacterial growth and in 1871 Joseph Lister conducted experiments using
Penicillium glaucium showing an antibacterial effect. See Mudgill
Penicillin and all members of the penicillin class of antibiotics are derivatives of
6-aminopenicillanic acid with a β-lactam ring structure responsible for their antimicrobial
activity. They work by attaching to enzymes called penicillin binding proteins (PBPs) that
play a key role in the synthesis of the peptidoglycan cell wall. The binding of penicillin
to these PBPs inhibits peptidoglycan cross link formation in bacterial cell wall synthesis.
—Methicillin: Both modification to PBPs and the presence of enzymes that can cleave the β-lactam ring structure are known resistance methods found in bacteria. In fact, by 1957, more than 80% of hospitals reported the presence of penicillin resistant strains of S. aureus. It was
this resistance that prompted more research into alternative antibiotics. By the end of the
1950s semi-synthesis around the 6-aminopenicillanic acid core of penicillins presented
a new class of penicillinase resistant penicillins including methicillin.
–Amoxicillin: is used to treat a wide variety of bacterial infections. It is a penicillin-type antibiotic that works by stopping the growth of bacterial. Amoxicillin is a widely utilized beta-lactam antimicrobial drug approved by the U.S. Food and Drug Administration (FDA) for use in the primary care setting. Amoxicillin is an aminopenicillin created by adding an extra amino group to penicillin to battle antibiotic resistance. This drug is indicated for the treatment of infections caused by susceptible isolates of selected bacteria, specifically those that are beta-lactamase–negative, including ear, nose, and throat infections, Helicobacter pylori eradication, lower respiratory and urinary tract infections, acute bacterial sinusitis, and skin and structure infections.
Amoxicillin is effective against a wide range of gram-positive bacteria, offering additional coverage against some gram-negative organisms compared to penicillin. Amoxicillin’s spectrum of activity includes coverage against Streptococcus species, with heightened efficacy against Listeria monocytogenes and Enterococcus spp. Furthermore, amoxicillin also demonstrates effectiveness against Haemophilus influenzae, select Escherichia coli strains, Actinomyces spp., Clostridium species, Salmonella spp., Shigella spp., and Corynebacteria spp.
Methylenomycins are highly functionalized cyclopentanone antibiotics produced by Streptomyces coelicolor A3.
—Methylenomycin A is an antibiotic that targets the bacterial cell wall, though its precise molecular mechanism is still being investigated. It acts against various Gram-positive and some Gram-negative bacteria by interfering with this structure, with recent studies highlighting its related, more potent compounds. it is an unusual antibotic produced by the model Actinomycete Streptomyces coelicolor A3 with a wide spectrum of antibiotic activity, including against diverse Gram-positive bacteria and Gram-negative Proteus.
–Pre-methylenomycin C lacton: is an intermedaite chemical in the natural process that produces methylenomycin A. By deleting biosynthetic genes, researchers disclosered two previously unkown biosyntehtic intermediates, both of which were much more potent antibiotics than methylenomycin A. One of the intermedaites, pre-methylenomycin C lacton was shown to be over 100 times more active against diverse Gram-positive bacteria than the original antibiotic methylenomycin A. It was.s hown to be effective against Staphylocccus aureus and Enterococcus faecium, the bacterial species bheind MRSA and VRE respectively. Importantly, the researchers could not detect any emergence of resistance to pre-methylenonycin C lacton in Enterococcus bacteria under conditions where vacomycin resistance is observed. (“Discovery of Late intermedaites in Methylenomycin Biosyntehsis Active agaist Drug-resistant Gram-positive bacterial pathogens”).
Drugs which Interfer/Target DNA or RNA:
Fluoroquinolones: Fluoroquinolones inhibit DNA unwinding enzymes or helicases, thereby stopping DNA transcription.
–Ciprofloxacin: is a member of the fluorquinolone drug class that is sued to treat various Gram-engative bacteria such as Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae and E coli and Gram-positive bacteria such as Staphylococcus auereus. (Chegini, “Bacteriophages: The promising therapeutic approach for enhancing ciprofloxacin efficacy against bacterial infection” J Clin Lab Anal, 2023).
Gepotidacin: This antibiotic is in phase III (GSK). It could become the first novel oral antibotic treatment for uncomplicated urinary tract infections in over 20 years. Gepotidacin provides activity against most srains of E. coli, including isolates that are highly resitant to current antibiotics. It binds to two different enzymes, which would reuqire the bacteria to develop mutations in both enzymes to become resistant . GSK also has an exclusive licence with Spero Therapeutics for another antibiotic to treat complicated urinary tract infections called tebipenem pivoxil hydrobromide (tebipenem HBr). This drug belogs to a class of antibiotic agents called carbapenems, which are typically reserved for sever bacterial infections of suspecte mutlidrug-resistant bacterail infections.
Antibiotics which Intefer with Protein Synthesis:
Macrolide antibiotics: such as erthyromycine were introduced to content with the problem of methicillin resistance and are widely used for the treatment of Gram-positive infections. The macrolides and related antibiotics act by binding at different sites in the peptide exit tunnel of the 50S ribosome subunit. Resistance can occur by modificaiton of the RNA or protein components of the tunnel.
Macrolide antibotics are well-characterized antimicrobials with excellent activity against many Gram-postive microorganisms. However, significant resistance against the most commonly used ompounds, i.e., erythromycin, clarithromycin and azithromycin has developed in many organisms.
–Ketolides are semisynthetic derivatives of macrolide antibiotics which are effective against certain resistant organisms. They lack the claidnose sugar of macrolides and contain a bridged 11, 12-aryl side chain. Ketolides exhibit significantly tighter binding to t e 50S ribosomal subunits of different microorganisms and cethromycin have shown improved activity against macrolide-resistant organisms. (Champney “Solithromycin inhibition of protein synthesis and ribosome biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae” Antimicrobial Agents and Chemotherapy, 57(4), 1632-1637, April 2013)
—-Fluoroketolides:
——Solithromycin (CEM-101) is a novel fluoroketolide with improved antimicrobial effectiveness. As a fluoroketolide, its activity against macrolide resistant organisms is enchanced by the addition of an alkyl-aryl side chain allowing tighter bidning tot he ribosome, thus overcoming acquired and cross-resistance obtained through posttranscriptional methylation of the 23rRNA in the 50S ribosomal subunit. In addition, the fluorine at the C-2 position of the 14 membered macrocyclic lactone allows for tighter binding, resulting in lower MICs. Its site of binding to the Escherichia coli 50S subunit has been characterized. This interaction inhibits protein biosynthesis and should impaire bacterial ribosomal subunit formation, much like with other ketolides. (Champney “Solithromycin inhibition of protein synthesis and ribosome biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae” Antimicrobial Agents and Chemotherapy, 57(4), 1632-1637, April 2013)
Aminoglycosides: insert on sites on the 30S subunit and cause the misreading of the mRNA, leading to abnormal proteins.
—Streptomycin: was introduced in 1944 for the treatment of tuberculosis. Mutant strains of bacterium tuberculosis resistant to therapeutic concentrations of the antibiotic were found to arise during patient treatment.
Tetracyclines: such as Tetracyline block the attachment of tRNA on the A acceptor site and stop further protein synthesis.
Combination of antibiotics:
Antibiotic combination therapy is the application of two or more antibiotics and is widely sued in clinical settings to prevent the evolution of resistance. Compared to monotherpiees, such therapies can improve treatment efficiency, expand antibiotic coverage or reduce health damage ot humans. For example, beta-lactams are used in combination with aminoglycosides and fluoroquinolones for the treatment of gram-negative bacteria of sepsis and severe Pseudomonas infections.
Antibiotic adjuvants:
Antibiotic adjuvants can provide an alternative and complementary strategy that can target antibiotic resistance or enhcnace antibiotic action to restore or improve the antimicrobial activity of commonly used antibiotic. The adjuvants commonly used can be classified into beta-lactamase inhibitors, efflux pump inhibitors and outer membrane permeabilizers.
Antibiotic Resistance:
The gut microbioa in healthy adults is a reservoir for multiple ARGs. A major parte of the gut reistome has its origin in soil and water habitates, and some in food. As these populations had little exposure to antibiotics, their ubiquitous ARGs such as tetracylcine and several beta-lactam resistance genes are environmentally derived. Only a small fraction of ARGs pose a threat to human health. (Staley, “Long- and short-term effects of fecal microbiota transplantation on antibiotic reistance genes: results form a randomized placebo-controlled trial” (2024)
Antibiotic Treatment:
Duration of Treatment:
–C-Reactive Protein Guided Treatment:
Most patients with bacterial bloodstream infetions receive between 10-14 dyas of antibiotics, although these durations are based largely on expert opinion, and recent evidence from retrospective analyses and a randomized trail indicate clinical noninferiority between 7 and 14 day courses. (Huttner, “Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30 day clinical failure rate in patients with uncomplicated Gram-Negative bacteremia” JAMA, 2020; 323(21): 2160-2169).
Fixed antibotic durations provide straightforward guidance but do not take into acount host characteristics or treatment response. Given high diversity among pathogens and theri hosts, another approach would be to individualize durations via biomarker assisted guidance. Although procalcitonin provides guidance, this biomarker is not always availabe, affordable, or antibiotic sparking.(Huttner, “Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30 day clinical failure rate in patients with uncomplicated Gram-Negative bacteremia” JAMA, 2020; 323(21): 2160-2169).
C-reactive protein (CRP), an acute pahse protein released by hepatocytes to coactivate the complement system in response to antigenic and other stimuli, is a widely available, inexpensive, and highly senstive marker of the inflammatory state. (Huttner, “Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30 day clinical failure rate in patients with uncomplicated Gram-Negative bacteremia” JAMA, 2020; 323(21): 2160-2169).