PHL 424 Antimicrobials

8th Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Mupirocin (pseudomonic acid) is an antibiotic of the monoxycarbolic acid class, derived from a fermentation product of Pseudomonas fluorescens

It shares no structural homology with other antibiotics in clinical practice and consists of a short fatty acid (nonanoic acid) ester linked to monic acid, with the tail portion closely resembling the isoleucyl moiety of the isoleucyl-adenylate reaction intermediate (Ile-AMP)

Inhibitors of bacterial protein synthesis,Mupirocin

Mechanism of Action Mupirocin inhibits bacterial protein synthesis by reversible binding and

inhibiting bacterial isoleucyl transfer-RNA synthetase, with subsequent inhibition of the incorporation of isoleucine into bacterial proteins

This is because the tail portion of monic acid closely resembles the isoleucyl moiety of the isoleucyl-adenylate reaction intermediate (Ile-AMP)

Because this mechanism of action is not shared with any other antibiotic, mupirocin has few problems of antibiotic cross-resistance

Mupirocin is currently the only clinically available aminoacyl-tRNA synthetase inhibitor and therefore acts as the model for the prospective clinical development of future aminoacyl-tRNA synthetase inhibitors

Mupirocin, Mechanism of Action

Resistance, Low-level resistance MuL (MIC up to 100 g/L), which is not clinically

significant, that is due to mutations of the host gene encoding isoleucyl transfer-RNA synthetase or an extra chromosomal copy of a gene encoding a modified isoleucyl transfer-RNA synthetase

High-level resistance MuH (MIC >1000 g/L) is mediated by a plasmid or chromosomal copy of mupA gene, which encodes a "bypass" synthetase that binds mupirocin poorly

Mupirocin is not a viable antibiotic against MuH strains. Other antibiotics such as nitrofurazone, silver sulfadiazine were shown to be effective against MuH strains

The mechanism of mupirocin differs from other clinical antibiotics, rendering cross-resistance to other antibiotics unlikely

However, the MupA gene may co-transfer with other antibacterial resistance genes. This has been observed already with resistance genes for triclosan, tetracycline and trimethoprim

Mupirocin, Resistance & Pharmacokinetics

Pharmacokinetics Systemic absorption through intact skin or skin lesions is minimal It is rapidly inactivated after absorption, as it is rapidly metabolized to monic acid

(inactive against bacteria), & hence, its clinical use is restricted to topical applications

Mupirocin, Antibacterial Activity & Uses

Antibacterial Activity Mupirocin is active against many gram-positive and selected gram-negative bacteria It has good activity with MICs of <1 μg/ml against Streptococcus pyogenes and

methicillin-susceptible and methicillin-resistant strains of S. aureus It is bactericidal at concentrations achieved with topical application Mupirocin cannot be used for extended periods of time, or indiscriminately, as

resistance does develop, and could, if it becomes widespread, destroy mupirocin's value as a treatment for MRSA

Uses Mupirocin is available as a 2% cream and ointment for dermatologic use and as a 2%

ointment for intranasal use

The dermatologic preparations are indicated for treatment of traumatic skin lesions and impetigo secondarily infected with S. aureus or S. pyogenes

The nasal ointment is approved for eradication of S. aureus nasal carriage. Mupirocin is highly effective in eradicating S. aureus carriage

• Mupirocin is currently the world's most widely used topical antibiotic for the control of MRSA

Mupirocin, Adverse Effects

Mupirocin may cause irritation and sensitization at the site of application Contact with the eyes should be avoided because mupirocin causes tearing,

burning and irritation that may take several days to resolve Systemic reactions to mupirocin occur rarely, if at all

Polyethylene glycol present in the ointment can be absorbed from damaged skin Application of the ointment to large surface areas should be avoided in patients with

moderate to severe renal failure to avoid accumulation of polyethylene glycol