BETA-LACTAMASE INHIBITORS

Question 1

Initial combinations of β-lactamase-resistant and β-lactamase-sensitive penicillins had limited success.

Failures were due to poor penetration, reversible binding, and β-lactamase induction

Answer 1

Early Challenges in β-Lactamase Inhibitor Therapy:

Question 2

Breakthrough Discovery
β-Lactamase Inhibitor

Answer 2

Clavulanic acid
sulbactam and tazobactam.
Thienamycins

Question 3

a naturally occurring β-lactamase inhibitor) led to renewed interest in combination therapy.

Answer 3

Clavulanic acid

Question 4

(natural β-lactams) inhibit β-lactamases and bind to PBPs.

Answer 4

Thienamycins

Question 5

mimic the substrate but cause irreversible enzyme inhibition (“suicide substrates”).

Answer 5

Mechanism-based inhibitors

Question 6

(e.g., clavulanic acid, sulbactam) → Prolonged inactivation via a heteroatom leaving group.

Answer 6

Class I inhibitors

Question 7

e.g., carbapenems) → Transient inhibition without a leaving group.

Answer 7

Class II inhibitors

Question 8

Are used with β-lactam-sensitive penicillins to treat β-lactamase-producing bacteria.

Answer 8

Clavulanic acid, sulbactam, tazobactam

Question 9

(a Class II inhibitor) has potent antibacterial activity along with β-lactamase inhibition.

Answer 9

Imipenem

Question 10

Group A β-lactamases (serine enzymes)

Answer 10

Generally inactivated by Class I inhibitors.

Question 11

Group C β-lactamases (cephalosporinases)

Answer 11

Resistant to Class I inhibitors.

Question 12

Group B metallo-β-lactamases (Zn²⁺-dependent)

Answer 12

Not inactivated by Class I inhibitors.

Question 13

an antibiotic isolated from Streptomyces clavuligeris.

Structurally, it is a 1-oxopenam without the 6-acylamino side chain of penicillins.

Contains a 2-hydroxyethylidene moiety at C-2.

Answer 13

Clavulanic acid

Question 14

Weak antibacterial activity, similar to 6-APA, making it useless as a standalone antibiotic.

Potent inhibitor of S. aureus β-lactamase and plasmid-mediated β-lactamases in Gram-negative bacteria.

Answer 14

Clavulanic acid

Question 15

a penicillanic acid sulfone (1,1-dioxopenicillanic acid).

A synthetic penicillin derivative that inhibits β-lactamases from S. aureus and many Gram-negative bacilli.

Answer 15

Sulbactam

Question 16

Weak intrinsic antibacterial activity.

Enhances the activity of ampicillin and carbenicillin against β-lactamase-producing bacteria (S. aureus, Enterobacteriaceae).

Answer 16

Sulbactam

Question 17

a penicillanic acid sulfone, structurally similar to sulbactam.

More potent β-lactamase inhibitor than sulbactam and has a broader spectrum than clavulanic acid.

Answer 17

Tazobactam

Question 18

a β-lactam antibiotic first isolated by Merck from Streptomyces cattleya.

Shares structural features with penicillins and cephalosporins:

Fused bicyclic ring system with a β-lactam and a 3-carboxyl group.

Answer 18

Thienamycin

Question 19

Broad-spectrum activity against aerobic and anaerobic Gram-positive & Gram-negative bacteria.

Highly active against S. aureus, P. aeruginosa, B. fragilis.

Resistant to most β-lactamases, making it effective against penicillin- and cephalosporin-resistant strains.

Answer 19

Thienamycin

Question 20

a chemically stable derivative of thienamycin, where the primary amino group is modified to prevent nucleophilic activity.

Cilastatin is a DHP-I inhibitor, preventing renal degradation

Answer 20

Imipenem

Question 21

The combination (Primaxin) ensures chemical & enzymatic stability but still has a short half-life (~1 hour) due to renal secretion.

Answer 21

Imipenem

Question 22

Broad-spectrum activity, similar to thienamycin.

Binds to PBPs (1b & 2), inhibiting cell wall synthesis.

Highly resistant to most β-lactamases, including those from Gram-negative bacteria like P. aeruginosa, S. marcescens, and Enterobacter spp..

Answer 22

Imipenem

Question 23

Effective against:

Aerobic Gram-positive bacteria (S. aureus, S. epidermidis, enterococci, viridans streptococci).

Aerobic Gram-negative bacteria (E. coli, Klebsiella, Serratia, Providencia, Haemophilus, Citrobacter, Proteus, Morganella, Acinetobacter, Pseudomonas spp.).

Anaerobic bacteria (B. fragilis, Clostridium, Peptococcus, Peptidostreptococcus, Eubacterium, Fusobacterium).

Answer 23

Imipenem

Question 24

Some carbapenems (e.g., imipenem, biapenem) can form __________, which may enhance bacterial penetration.

Answer 24

zwitterions

Question 25

second-generation carbapenem with extensive clinical evaluation. Approved as Merrem for treating multiply-resistant bacterial infections and serious conditions like: Bacterial meningitis, septicemia, pneumonia, and peritonitis. Administered parenterally Stable against most β-lactamases, including some carbapenemases.

Answer 25

Meropenem

Question 26

Second-generation carbapenem with properties similar to meropenem. Broad-spectrum activity against: Aerobic Gram-negative and Gram-positive bacteria Anaerobes parenteral administration

Answer 26

Biapenem:

Question 27

β-lactam antibiotics derived from Cephalosporium spp. or synthesized semisynthetically. Discovered in 1945 by Giuseppe Brotzu, who observed their activity against Gram-positive and Gram-negative bacteria.

Answer 27

Cephalosporins

Question 28

Abraham and Newton (1948) isolated three key components: Minimal antibacterial activity

Answer 28

Cephalosporin P1

Question 29

Abraham and Newton (1948) isolated three key components Penicillin N More effective against Gram-negative bacteria (e.g., Salmonella spp.) but less effective against Gram-positive bacteria than penicillin G.

Answer 29

Cephalosporin N

Question 30

Abraham and Newton (1948) isolated three key components: – Resistant to S. aureus β-lactamase but initially less potent than penicillins

Answer 30

Cephalosporin C

Question 31

Semisynthetic Cephalosporins 7-ACA

Answer 31

(7-aminocephalosporanic acid)

Question 32

Goals of semisynthetic cephalosporins include:

Answer 32

Increased acid stability (for oral use). Better pharmacokinetics (e.g., improved absorption). Broader antimicrobial spectrum. Enhanced resistance to β-lactamases and better penetration. Lower allergenicity. Improved tolerance for parenteral administration.

Question 33

(prodrug of cefuroxime).

Answer 33

Cefuroxime axetil

Question 34

(prodrug of cefpodoxime).

Answer 34

Cefpodoxime proxetil

Question 35

β-lactamase-resistant that become active after metabolism.

Answer 35

alkoximino-cephalosporins

Question 36

the only cephalosporin that can be administered both orally and parenterally.

Answer 36

Cephradine

Question 37

-are broad-spectrum antibiotics with antibacterial effectiveness comparable to ampicillin. -more resistant to inactivation by β-lactamases, especially from Gram-positive bacteria, than ampicillin -exhibit uniquely potent activity against most Klebsiella species.

Answer 37

Cephalosporins

Question 38

-show different levels of resistance to β-lactamases depending on the enzyme's source and properties. -generally more resistant than most penicillins to hydrolysis by β-lactamases from S. aureus and Bacillus subtilis. This resistance is due to the cephem ring system, not the acyl group.

Answer 38

Cephalosporins

Question 39

Some inducible β-lactamases (Group C) which hydrolyze cephalosporins more rapidly than penicillins.

Answer 39

cephalosporinases

Question 40

resists β-lactam antibiotics primarily through: β-lactamase production (enzymatic degradation). Reduced penetration of the antibiotic through the bacterial cell envelope.

Answer 40

P. aeruginosa

Question 41

Effective Antipseudomonal Cephalosporins certain cephalosporins demonstrate useful activity against P. aeruginosa, including:

Answer 41

Cefoperazone Moxalactam Cefotaxime Ceftizoxime Ceftriaxone Ceftazidime

Question 42

associated with an increased risk of hypoprothrombinemia (vitamin K deficiency-related bleeding)

Answer 42

Cephalosporins

Question 43

Cephalosporins are categorized into:

Answer 43

first-, second-, third-, and fourth-generation based on: Time of discovery Antimicrobial properties

Question 44

(Keflex, Keforal) was specifically designed as an oral semisynthetic cephalosporin. -remains stable in acid -Recommended especially for urinary tract infections (UTIs) and sometimes for upper respiratory tract infections (URTIs). -Similar antibacterial activity to cephalothin and cephaloridine.

Answer 44

Cephalexin

Question 45

the only cephalosporin available in both oral and parenteral forms. -very similar to cephalexin and can be considered a partially hydrogenated derivative.

Answer 45

Cephradine

Question 46

a semisynthetic derivative of 7-ADCA with a D-hydroxyphenylglycyl group at the 7-acyl position. -Well absorbed orally, reaching 75–80% of the plasma levels of its structural analog, cephalexin. -Allows once-daily dosing, a key advantage over cephalexin.

Answer 46

Cefadroxil (Duricef)

Question 47

a semisynthetic cephalosporin introduced in the U.S. in 1979. -Synthesized via ozonolysis, followed by halogenation.

Answer 47

Cefaclor (Ceclor)

Question 48

-(Zinacef) belongs to the second generation, though it features methoximinoacyl substitution, a characteristic of many third-generation cephalosporins. - The syn-alkoximino group enhances β-lactamase resistance. -

Answer 48

Cefuroxime

Question 49

It is a lipophilic, acid-stable oral prodrug that is hydrolyzed to cefuroxime by intestinal and/or plasma enzymes during absorption.

Answer 49

Cefuroxime axetil (Ceftin)

Question 50

Prodrug of Cefpodoxime designed for oral administration. Hydrolyzed by esterases in the intestinal wall and plasma to release the active drug

Answer 50

Cefpodoxime proxetil (Vantin)

Question 51

Two Categories of Newer Cephalosporins

Answer 51

Orally active β-lactamase–resistant cephalosporins. Parenteral β-lactamase–resistant antipseudomonal cephalosporins.

Question 52

Chemically Novel Third-Generation Cephalosporin a unique analog of oximino cephalosporins. Resistant to β-lactamase hydrolysis Orally active with rapid & nearly complete absorption. Highest oral bioavailability among third-generation cephalosporins.

Answer 52

Ceftibuten (Cedax)

Question 53

Fourth-Generation Cephalosporin a parenteral, β-lactamase–resistant cephalosporin Potency matches first-generation cephalosporins against Gram-positive bacteria. Potency matches third-generation cephalosporins against Gram-negative bacteria. Excreted largely unchanged in the urine.

Answer 53

Cefpirome (Cefrom)

Question 54

Innovative siderophore cephalosporin with broad Gram-negative coverage.

Answer 54

GR-69153:

Question 55

MRSA-active cephalosporin with better killing speed than vancomycin.

Answer 55

TOC-039

Question 56

were first isolated from saprophytic soil bacteria in Japan and the United States.

Answer 56

Monobactams

Question 57

(SQ 26,445) was the first discovered but had weak antibacterial activity despite high β-lactamase resistance.

Answer 57

Sulfazecin

Question 58

became a successful monobactam antibiotic after optimizing structural modifications.

Answer 58

Aztreonam

Question 59

Monobactam antibiotic, synthesized completely Binds exclusively to PBP 3 in Gram-negative bacteria. Does not induce chromosomal β-lactamase production.

Answer 59

Aztreonam (Azactam)

Question 60

Newer monobactam that is orally active. Highly resistant to β-lactamases. Similar antibacterial spectrum to aztreonam.

Answer 60

Tigemonam

Question 61

was the first aminoglycoside, discovered in 1944 by Schatz and associates. Success led to further discoveries, primarily from Streptomyces species

Answer 61

Streptomycin

Question 62

Major Aminoglycosides (Marketed in the U.S.) Naturally occurring:

Answer 62

Kanamycin Neomycin Paromomycin Gentamicin Tobramycin Netilmicin

Question 63

Semisynthetic Aminoglycosides

Answer 63

Amikacin (derived from kanamycin A)

Question 64

a related aminoglycoside, is only used for gonorrhea

Answer 64

Spectinomycin

Question 65

Named due to their amino sugars linked by glycosidic bonds. Contain at least one aminohexose and, in some cases, a pentose (e.g., streptomycin, neomycin, paromomycin).

Answer 65

aminoglycosides

Question 66

most effective against serious systemic infections caused by aerobic Gram-negative bacilli. Preferred agents: Kanamycin, gentamicin, tobramycin, netilmicin, amikacin

Answer 66

aminoglycosides

Question 67

Most effective for tuberculosis (TB), brucellosis, tularemia, and Yersinia infections.

Answer 67

Streptomycin

Question 68

Used mainly for amebic dysentery

Answer 68

Paromomycin

Question 69

aminoglycosides and β-lactams can have a synergistic effect:

Answer 69

β-lactam weakens the bacterial cell wall, allowing better aminoglycoside penetration.

Question 70

Primary Target: Bacterial Ribosomes bind to the 30S ribosomal subunit, inhibiting protein synthesis initiation. interfere with translation fidelity, leading to misreading mutations and incorporation of incorrect amino acids into proteins

Answer 70

Aminoglycoside

Question 71

equally effective at blocking initiation and causing misreading

Answer 71

Streptomycin

Question 72

inhibits initiation of protein synthesis but does not cause misreading.

Answer 72

Spectinomycin

Question 73

All aminoglycosides are bactericidal except

Answer 73

spectinomycin, which is bacteriostatic

Question 74

Aminoglycosides Resistance is commonly due to enzymatic inactivation by bacterial enzymes such as:

Answer 74

Aminoacetyltransferases (AAC) → Acetylate amino groups. Phosphotransferases (APH) → Phosphorylate hydroxyl groups. Nucleotidyltransferases (ANT) → Adenylate hydroxyl groups.

Question 75

are naturally resistant due to the lack of respiration-driven transport mechanisms required for aminoglycoside uptake.

Answer 75

Anaerobic bacteria

Question 76

enable resistance to spread between bacterial species via conjugation (direct contact).

Answer 76

Plasmid-encoded R factors