**Conflict of interest**

*Pseudomonas aeruginosa - An Armory Within*

lysis, followed by MltG.

maintenance.

**infections**

**8. Conclusions**

resistant *P. aeruginosa*.

**Acknowledgements**

U.S. Department of Veteran Affairs.

possibilities in the future antibiotic arsenal.

9 hours. Some of the other knockouts demonstrated minor bulge formation (MltA, MltG, MltF, SltB1, SltB3) at 9 hours but none showed cell lysis. The effect was even more dramatic in terms of rapidity of bulge formation and cell lysis when meropenem was used. In fact, this semi-qualitative assay that involves spotting the bacteria and β-lactam at a given distance onto agar had to be modified for meropenem, as lysis occurred too quickly compared to conditions for ceftazidime. In the case of meropenem, an inhibitor of PBP2, Slt showed the greatest bulge formation and

The soluble forms of five of the Lt enzymes were purified and bulgecin A binding constants measured: Slt Kd = 8.5 ± 1.1 μM; MltD Kd = 1.4 ± 0.3 μM; MltG

Dik et al*.* [27] also demonstrated via scanning electron microscopy that cell wall failure within the bulge is responsible for cell lysis, in the presence of β-lactams and Bulgecin A. Withdrawal of the β-lactam antibiotic leads to delayed recovery of cell morphology in the presence of Bulgecin A alone, suggesting further, the cooperative nature of the Lt and PBP functions in cell wall

**7. Future prospects for antibiotic enhancers to treat** *P. aeruginosa*

Now that the syntheses of the bulgecins A, B and C have been accomplished and purified Lt enzymes of many bacteria are available with simple commercial high throughput assays such as ENZCHEK lysozyme™ (substrate is a fluorescein labelled sacculus from *Micrococcus lutei*), it should not be long before potent derivatives of bulgecins are developed through medicinal chemistry approaches. Combinations of enhancers with novel β-lactamase inhibitor/potent anti-pseudomonal β-lactams are

Antibiotic resistance in *P. aeruginosa* is on the rise in both inpatient and outpatient settings. β-lactams remain among the most successful antibiotics due to their potency, efficacy and safety. Traditionally, β-lactamase inhibitors have proved able to extend the life of these valuable antibiotics. However, through a variety of resistance mechanisms, *P. aeruginosa* has eluded these approaches. Lts are novel cell wall enzymes that work in concert with PBPs to facilitate numerous cellular functions (insertion of secretion systems, cell division, etc.). When both Lts and PBPs are inhibited, bacteria exhibit abnormal bulging of cell wall and osmotic lysis. Bulgecins are naturally occurring compounds that inhibit Lts. Together with β-lactams, Bulgecin A can lead to effective bacterial killing, even when *P. aeruginosa* are resistant to the partner β-lactam antibiotics. Bulgecins are a novel β-lactam enhancer that may prove beneficial in the treatment of infections with

The author would like to acknowledge her affiliation and employment with the

Kd = 24 ± 5 μM, SltB1 Kd = 160 ± 20 μM; RlpA Kd = 1200 ± 280 μM.

**78**

The author is an employee of the U.S. Department of Veterans Affairs. The opinions expressed in this review are her own and do not reflect those of her employer.
